Animal models, screening methods, and treatment methods for intraocular diseases or disorders

Abstract

This application provides a screening method and animal model related to intraocular diseases, such as age-related macular degeneration (AMD), for identifying candidate therapeutic agents for treating or preventing eye diseases, such as AMD. [Solution] The present application also provides compounds / compositions that can kill or inhibit the growth of microorganisms such as Bacillus megatherium. The present application further provides methods for treating infections caused by microorganisms such as Bacillus megatherium, and for treating or preventing diseases or disorders associated with such infections, such as AMD, using the compounds / compositions.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to International Application No. PCT / CN2019 / 070572 filed on 7 January 2019, International Application No. PCT / CN2019 / 084369 filed on 25 April 2019, and Chinese Patent Application No. 201811351660.9 filed on 14 November 2018, and the disclosures of any of these patents are incorporated by reference for all purposes.

[0002] The present invention generally relates to the technical field of diagnosis and treatment of eye diseases, and more specifically to screening methods, animal models, and methods for treating or preventing eye diseases or disorders. In some embodiments, the disclosure further relates to compounds, compositions, and methods for treating and / or preventing age-related macular degeneration (AMD) in subjects, such as human patients or vertebrates, such as dogs, cats, horses, or monkeys. [Background technology]

[0003] The eyes are truly the most vital windows to the soul. People use their eyes every day, yet they are very fragile. Various factors can easily cause eye discomfort and disease. Common eye diseases include conjunctivitis and dry eye syndrome, while more serious intraocular diseases or disorders include cataracts (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), and uveitis.

[0004] Among older adults, age-related macular degeneration (AMD) is the leading cause of irreversible vision loss worldwide. It is characterized by confluent soft drusen and / or early-stage macular retinal pigment changes (intermediate AMD) deposited between the retinal pigment epithelium (RPE) and Bruch's membrane. In later stages, advanced AMD is characterized by two main subtypes: macular geographic atrophy (dry AMD) and macular choroidal neovascularization (wet AMD). While anti-VEGF therapies have been used to control wet AMD, there are currently no approved therapies for dry AMD.

[0005] The pathogenesis of AMD involves both genetic and environmental factors. Currently, the environmental factors that cause local inflammation and lead to early soft drusen are not clear in the pathology of AMD. Numerous studies have identified changes in gene loci associated with AMD susceptibility, such as complement factor H (CFH), age-related macular susceptibility 2 (ARMS2), and HtrA serine peptidase 1 (HTRA1), suggesting that AMD may be an inflammatory disease.

[0006] Currently, the environmental factors that cause local inflammation and lead to early soft drusen formation are not clearly understood in the pathology of AMD. There is a need for improved compositions and methods for evaluating, treating, or preventing intraocular diseases or disorders in subjects, such as mammals or humans. This disclosure addresses these needs and other related needs. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In several embodiments, the present invention relates to screening methods and animal models for multiple types of eye diseases, such as human eye diseases. These screening methods and animal models are based in part on the unexpected discovery that the intraocular environment is not sterile and that some intraocular microbiota, such as Bacillus megatherium, can be the cause of multiple types of eye diseases, such as AMD. [Means for solving the problem]

[0008] In some embodiments, the present invention provides a screening method for identifying candidate therapeutic agents for treating or preventing eye diseases, such as AMD. The screening method may be, for example, an in vitro screening method in a culture dish, or an in vivo screening method using, for example, an animal model described in this application.

[0009] In some embodiments, the present invention provides a screening method comprising the steps of: a) culturing a microorganism in a suitable medium in the presence of a test compound; b) measuring the growth of the microorganism in the medium in the presence of the test compound; and c) optionally identifying a candidate therapeutic agent that inhibits the growth of the microorganism compared to a control. In some embodiments, the microorganisms include species that are concentrated in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of subjects with eye diseases rather than healthy subjects, and the eye diseases are selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. In some embodiments, the subjects are human subjects. In some embodiments, the method identifies candidate therapeutic agents for treating or preventing human eye diseases such as AMD, BD, Cat, EOS, GLA, VKH, or combinations thereof.

[0010] In some specific embodiments, the screening method identifies candidate therapeutic agents for treating or preventing AMD. In some embodiments, the microorganisms include species that are more concentrated in the intraocular space (e.g., aqueous humor, vitreous fluid, soft drusen) of subjects with AMD than in healthy subjects. In some embodiments, the microorganisms include Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, and Cytophaga huchinsonii. The microorganism comprises one or more species selected from Bacillus hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the microorganism comprises Bacillus megatherium and / or Pseudomonas putida. In some embodiments, the microorganism comprises at least Bacillus megatherium. In some embodiments, the microorganism comprises a mixture of microbial species, which are substantially similar to those observed in the aqueous humor, vitreous fluid, and / or soft drusen of subjects suffering from AMD. In some embodiments, the microorganism is derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from age-related macular degeneration.

[0011] Screening methods for identifying candidate therapeutic agents for treating or preventing other eye diseases, such as BD, Cat, EOS, GLA, and VKH, are similar to those described for AMD, but use different microorganisms as described in detail hereof. For example, in the case of BD, the microorganisms cultured in the presence of the test compound may typically include one or more species selected from Sphingomonas wittichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, and Meiothermus silvanus (D). In the case of Cat, the microorganisms cultured in the presence of the test compound are typically Pseudomonas mendocina and Kytococcus sedentarius. It may include one or more species selected from *Pteridium sedentarius*, *Alicycliphilus denitrificans*, *Achromobacter xylosoxidans*, *Sphingobium japonicum*, *Mycobacterium abscessus*, *Arthrobacter aurescens*, *Prevotella dentalis*, *Sinorhizobium meliloti*, and *Acidovorax ebreus*. In the case of GLA, the microorganisms cultured in the presence of the test compound may typically include one or more species selected from Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Dyadobacter fermentants, and Serratia marcescens. In the case of VKH, the microorganisms cultured in the presence of the test compound may typically include Escherichia coli. The microorganisms used in the screening method may include one or more species selected from coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimucosum, and Finegoldia magna. In some embodiments, the microorganisms used in the screening method may include a mixture of microbial species, each substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from BD, Cat, EOS, GLA, or VKH. In some embodiments, the microorganisms used in the screening method may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from BD, Cat, EOS, GLA, or VKH.

[0012] The screening method of this application is not limited to any particular test compound or any type of test compound. Several exemplary test compounds are described herein. The screening method of this application may be a low-throughput, medium-throughput, or high-throughput method, and parallel testing of multiple test compounds may be performed as needed. Identification in the screening method is also not limited to any particular technique. For example, in some embodiments, identification includes the identification of candidate therapeutic agents that prevent visible growth of microorganisms below the maximum test concentration. In some embodiments, identification includes the identification of candidate therapeutic agents that prevent visible colonization of microorganisms below the maximum test concentration.

[0013] The screening method of the present invention may further include the step of determining or having determined one or more microbial species that are concentrated in the intraocular space of subjects suffering from eye diseases more than healthy subjects, the eye diseases being selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. For example, in some embodiments, the present invention provides a screening method comprising the steps of: a) determining or having determined one or more microbial species that are concentrated in the intraocular space of subjects suffering from age-related macular degeneration (AMD) more than healthy subjects; b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control.

[0014] Some embodiments of the present invention relate to a method for preparing animal models of eye diseases according to the present application. Animal models are typically used for human eye diseases. Animal models prepared by the above method are also embodiments of the present invention.

[0015] Typically, the method for creating an animal model involves introducing microorganisms and / or inactivated proteins derived from such microorganisms into the intraocular space of an animal's eye, wherein the microorganisms include species that are more concentrated in the intraocular space of subjects with eye diseases than in healthy subjects, and the eye diseases are selected from cataracts (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), endophthalmitis (EOS), and combinations thereof, and the introduction induces one or more symptoms of the eye disease.

[0016] In some specific embodiments, the present invention provides a method for creating an animal model of AMD. In some embodiments, the method includes the step of introducing a microorganism and / or an inactivated protein derived from the microorganism into the intraocular space of an animal's eye, wherein the microorganism is a species that is more concentrated in the intraocular space of subjects with AMD than in healthy subjects, and the introduction induces one or more symptoms of AMD. The method typically involves introducing live microorganisms into the intraocular space of an animal. In some embodiments, the microorganisms to be introduced include at least live Bacillus megatherium. Preferably, the animal is a non-human primate (e.g., a monkey). In some embodiments, the animal is a rhesus macaque.

[0017] The AMD animal models prepared in this application may also be used to identify candidate therapeutic agents for treating or preventing AMD. For example, in some embodiments, the present invention also provides a screening method comprising the steps of: a) administering a test compound to an AMD animal model as described in this application; b) determining the severity of one or more symptoms of eye disease after administration; and c) optionally identifying candidate therapeutic agents that alleviate at least one of the symptoms compared to a control.

[0018] In some embodiments, the present invention also provides a method for treating or preventing the aforementioned eye disease, e.g., AMD, of the present application. In some embodiments, the method includes administering to a subject in need an effective dose of any candidate therapeutic agent for the corresponding eye disease, e.g., AMD, identified by any screening method of the present application.

[0019] In some embodiments, the Disclosure relates to a plurality of compounds and / or compositions comprising such compounds that can kill or inhibit the growth of microorganisms associated with AMD, such as Bacillus megatherium. In some embodiments, the Disclosure provides compounds of any one of formulas I, II, III, IV-1, IV-2, V as defined herein and any subformula thereof, or pharmaceutically acceptable salts or esters. In some embodiments, the Disclosure provides any of compounds 1 to 8, or pharmaceutically acceptable salts or esters. In some embodiments, the compounds of the Disclosure may be derived from synthetic sources. In some embodiments, the compounds of the Disclosure may be isolated compounds or substantially pure compounds.

[0020] In some embodiments, the present invention relates to a pharmaceutical composition comprising one or more compounds of the present disclosure and any pharmaceutically acceptable excipient. For example, in some embodiments, the pharmaceutical composition comprises a compound of formula I, II, III, IV-1, IV-2, V, any subformula thereof, or any of compounds 1 to 8, or a pharmaceutically acceptable salt or ester, for example, in an amount effective to kill or inhibit the growth of the microorganism of the present invention, such as Bacillus megatherium, in, for example, the eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestines, of a subject. The pharmaceutical composition of the present invention may be prepared to be delivered via any known route of delivery, such as oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous administration. In some embodiments, the pharmaceutical composition of the present invention may further comprise, for example, an antibiotic and / or an anti-VEGF agent, as described in the present invention.

[0021] In several embodiments, the Disclosure further provides methods for treating infections of the microorganisms of the Application, such as Bacillus megatherium (e.g., eye infections, e.g., in the intraocular space), and for treating or preventing diseases or disorders associated with such infections (e.g., AMD), using the compounds of the Disclosure or the pharmaceutical compositions of the Application.

[0022] In some embodiments, the Disclosure provides a method for killing or inhibiting the growth of the microorganism of the Application, such as Bacillus megatherium, in a subject who requires it. In some embodiments, the method includes administering a therapeutically effective dose of a compound of the Disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any subformula thereof, or any of compounds 1 to 8, or pharmaceutically acceptable salts or esters, or the pharmaceutical compositions of the Application) to a subject. In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject's eye is infected with the microorganism, such as Bacillus megatherium. In some embodiments, the method further includes identifying, or having identified, that the subject is infected with the microorganism, such as Bacillus megatherium, for example, in the intraocular space. In some embodiments, the subject is further administered an antibiotic and / or an anti-VEGF agent, for example, as described in the Application.

[0023] In some embodiments, the Disclosure provides a method for treating or preventing AMD in a subject who requires it. In some embodiments, the method includes administering a therapeutically effective dose of a compound of the Disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any subformula thereof, or any of compounds 1-8, or pharmaceutically acceptable salts or esters) to a subject. In some embodiments, the method further includes administering an antibiotic and / or anti-VEGF agent to a subject, for example, as described in the Application. In some embodiments, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen, and / or degraded drusen), for example, dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method further includes identifying, or having identified, that a subject is infected with a microorganism of the Application, such as Bacillus megatherium, in the intraocular space, for example. In some embodiments, the subject is infected with the microorganism of the present invention, such as Bacillus megatherium, for example, in the intraocular space.

[0024] In some embodiments, the Disclosure provides methods using TCM extracts having antimicrobial activity. In some embodiments, the methods are for killing or inhibiting the growth of the microorganisms of the Application in a subject requiring such treatment, such as Bacillus megatherium infection (e.g., eye infection, e.g., in the intraocular space), or for treating or preventing AMD. In some embodiments, the methods include administering to a subject an extract derived from one or more TCMs selected from licorice (e.g., Glycyrrhiza uralensis), pycnostemium (e.g., Cynanchum otophyllum), forsythia suspense, cinnamon bark (e.g., Citrus aurantium L.), rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch), citrus peel (e.g., Citrus reticulata Blanco), and citrus fruit (e.g., Panax notoginseng). In some embodiments, the method further includes identifying, or having identified, that a subject is infected with the microorganism of the present application, e.g., Bacillus megatherium, for example, in the intraocular space. In some embodiments, the subject is infected with the microorganism of the present application, e.g., Bacillus megatherium, for example, in the intraocular space. The extract may be an extract of a single TCM or an extract of one or more TCMs. Typically, the extract is an aqueous extract. In some embodiments, the extract may exist in liquid, semi-solid, or solid form or any other form. In some embodiments, for example, as described herein, the subject is further administered an antibiotic and / or an anti-VEGF agent.

[0025] In some embodiments, the Disclosure provides a method for treating an infection of the microorganism of the Application, e.g., Bacillus megatherium (e.g., an eye infection, e.g., in the intraocular space), or for treating or preventing AMD, using an antibiotic to kill or inhibit the growth of the microorganism in a subject who needs it. In some embodiments, the method includes the step of administering an effective amount of antibiotic to a subject, e.g., as described in the Application. In some embodiments, any commercially available antibiotic, e.g., an antibiotic approved by the U.S. FDA, may be used. In some embodiments, the method further includes the step of identifying, or having identified, that a subject is infected with the microorganism of the Application, e.g., Bacillus megatherium, e.g., in the intraocular space. In some embodiments, the subject is infected with the microorganism of the Application, e.g., Bacillus megatherium, e.g., in the intraocular space. In some embodiments, the subject is further administered an anti-VEGF drug, e.g., as described in the Application.

[0026] The administration of the present invention is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, topical, intravitreous, intramuscular, subcutaneous, or intravenous.

[0027] Furthermore, the above-mentioned summary and the following detailed explanation are merely illustrative and interpretive and do not limit the invention of this application. [Brief explanation of the drawing]

[0028] [Figure 1] The susceptibility of Bacillus megatherium to multiple antimicrobial agents is illustrated. [Figure 2] The culture in liquid cooked meat medium coated with liquid paraffin is illustrated. [Figure 3] This describes the detection of bacteria in cultures under a standard optical microscope. E. coli cultured under an optical microscope is observed. The negative control consists of sample preparation buffer inoculated with either AH or VH. Bacteria in AH or VH samples (samples of culture-positive and negative samples) cultured under an optical microscope are observed. [Figure 4] The images show the eye surface and fundus of rhesus macaques before and after bacterial inoculation (Propionibacterium acnes (P. acnes) and Bacillus megatherium). Propionibacterium acnes and Bacillus megatherium were inoculated into the right eye (OD) and left eye (OS), respectively. The images show the eye surface and fundus before bacterial inoculation and 3 days after inoculation. [Figure 5] The images show the eye surface and fundus of rhesus monkeys before and after inoculation with bacteria (Propionibacterium acnes and Pseudomonas putida). The right eye (OD) and left eye (OS) of the rhesus monkeys were inoculated with Propionibacterium acnes and Pseudomonas putida, respectively. The images show the eye surface and fundus before bacterial inoculation and 3 days after inoculation. [Figure 6] The anatomy and retinal location of subretinal injections are illustrated. [Figure 7] The image shows the fundus of a rhesus monkey 47 days after injection, which received subretinal inoculation of 20 CFU of AH culture, VH culture, and Bacillus megatherium. [Figure 8] This diagram illustrates how antibiotic treatment can alter bacteria-induced dorusenoid lesions in monkey retinal tissue. [Figure 9] This figure illustrates highly enriched species in the intraocular metagenomics of patients with cataracts, AMD, glaucoma, BD, and VKH, as identified using LefSe. [Figure 10] Each of compounds 1-8 effectively controls the growth of Bacillus megatherium. Test conditions: 1 mg of compound, Bacillus megatherium, 15 ml of culture medium, resulting in a concentration of 1 × 10⁵ cells / 100 μl. [Modes for carrying out the invention]

[0029] In several embodiments, this disclosure is based in part on the surprising discovery that the intraocular environment is not sterile and that certain intraocular microbiomes can be the etiologists of multiple eye diseases, such as AMD. Such initial discoveries, detailed in PCT application number PCT / CN2018 / 112022, filed October 26, 2018, titled "METHODS AND COMPOSITIONS FOR ASSESSING AND TREATING INTRAOCULAR DISEASES AND DISORDERS" (the content of which is incorporated by reference in whole), found that such microorganisms, such as Bacillus megatherium, when administered alive, can activate the complement system in vivo in rhesus monkeys and induce dorsenoid lesions. Furthermore, killing or inhibiting the growth of such microorganisms, for example by intravitreal administration of the antibiotic vancomycin, can reduce the size of dorsenoid lesions in the retinal tissue of rhesus monkeys compared to controls. See also Example 9 of this application. These data and results demonstrate that drugs capable of killing or inhibiting the growth of such microorganisms, such as Bacillus megatherium, are useful in the treatment of age-related macular degeneration.

[0030] For example, as detailed in PCT application number PCT / CN2018 / 112022, metagenomic sequencing analysis was performed on aqueous humor (AH) samples from 41 patients with cataracts (Cat), 20 with acute mesenteric dysplasia (AMD), 18 with glaucoma (GLA), 9 with Behçet's disease (BD), 9 with Vogt-Koyanagi-Harada syndrome (VKH), and 8 with endophthalmitis (EOS). Interestingly, despite bacteria being the dominant component of the intraocular human microbiome in all six patient types, both the α-diversity and homogeneity of the intraocular microbial community differed significantly. Significant differences existed among patients with cataracts, EOS, and some with glaucoma, as shown by principal component analysis (PCA) performed on the composition of the intraocular microbiota (all microbial species were used). However, patients with AMD, VKH, BD, and some with glaucoma shared indistinguishable features in the intraocular human microbiome. Similarly, as is evident from hierarchical cluster analysis of the abundance ratios of functional microbial genes from all metagenomics, each eye exhibits general characteristics of microbial function, while each disease group contains outliers that can be classified into other disease clusters. Regardless of the pronounced individuality of the intraocular human microbiome, characteristic bacterial species can be identified for each eye disease group tested. In short, as is evident from the results obtained, eye diseases such as AMD, cataracts, glaucoma, BD, VKH, and EOS can be distinguished by the composition and function of the intraocular microbiome.

[0031] Using metagenomic analysis, we identified 14 bacterial species that were highly enriched in AH (arthritis of the heart) of AMD patients. Although Propionibacterium acnes was the most abundant microorganism in AH of AMD patients, Bacillus licheniformis and Bacillus megaterium were the most enriched species among the 14 AMD-specific species in AMD AH specimens. Next, we performed PCR analysis to investigate whether the 14 AMD-specific bacteria could be detected in rigid or soft drusen tissue compared to non-drusen retinal tissue from six archived eye slides from AMD patients. As a result, only 8 bacteria were detected, among which Propionibacterium acnes was the most abundant species, and Bacillus megaterium was the species enriched in soft drusen tissue. The relative abundance of Propionibacterium acnes in rigid drusen, soft drusen, and dry AMD lesion tissue is equivalent to that in non-drusen, non-lesional retinal tissue. Compared to non-drusen / non-lesional tissue, the relative abundance of Bacillus megatherium is approximately 18 times higher in soft drusen, but this is not the case in AMD lesions. These data reveal a possible role of Bacillus megatherium in drusen formation and the mechanisms of AMD development.

[0032] As is evident from previous studies, drusen contain multiple complement components and polysaccharides in addition to many other proteins. Furthermore, drusen components activate the inflammasome and promote the expression of IL-1β and IL-18. Therefore, the inventors first investigated whether Bacillus megatherium, a drusen component, can induce complement system activation in vitro and promote the secretion of IL-1β and IL-18 by acute retinitis pigmentosa-19 (ARPE19) cells. The inventors found that Bacillus megatherium, rather than Propionibacterium acnes, significantly increased pyroptosis of RPE cells in a time-dependent manner. Complement system activation was demonstrated by producing an active form of the C5A protein. Both bacteria induced CFH protein secretion by ARPE19 cells, while Bacillus megatherium's induction of CFH was more pronounced than that of Propionibacterium acnes. As a result of pyroptosis, in vitro infection with Bacillus megatherium, rather than Propionibacterium acnes, triggers the secretion of active IL-1β and IL-18 by RPE cells. As these results clearly indicate, Bacillus megatherium infection can cause inflammation similarly found in soft drusen.

[0033] Next, the inventors tested whether Bacillus megatherium can induce inflammation in vivo. The non-human primate rhesus macaque (Macaca fascicularis) is considered a model system that takes into account the anatomical structure of the eye and the intraocular environment shared by humans and rhesus macaques. Infection of the eye with live Propionibacterium acnes or inoculation with its ultrasonically inactivated protein did not induce significant intraocular inflammation. However, infection of the eye with live Bacillus megatherium, rather than protein, did induce significant intraocular inflammation. Intraocular inflammation induced by live Bacillus megatherium is characterized by elevated expression of TNFA and IL6, rather than IFNG and IL17A. Importantly, only live Bacillus megatherium can activate the complement system, including C5A and CFH, and induce pyroptosis cytokines IL-1β and IL-18 in vivo. The bacteria continued to survive in the eye after the inflammation began, indicating that intraocular inflammation can persist for a substantial period. In short, these data demonstrate that Bacillus megatherium infection can activate the complement system in vitro and in vivo over a long period and induce pyroptosis of eye cells.

[0034] Without being constrained by theory, the fact that bacteria such as Bacillus megatherium are present in drusen and activate a complement-mediated immune response can explain the diverse drusen formation between the RPE and Bruch's membrane. All major proteins found in drusen (including complement components such as C1Q and immunoglobulins) are first-line anti-infective agents. Other drusen proteins, such as vitronectin and apolipoprotein E, have recently been proven to be anti-infective agents. Therefore, drusen formation is likely a crucial response in the aging retina to control infiltrating bacterial pathogens. Due to bacterial diversity, the shape and size of drusen can vary. In the case of rigid drusen, they disappear once the infection is cleared. However, some pathogens, such as Bacillus megatherium, induce prolonged activation of the immune response in soft drusen, leading to damage to RPE cells and photoreceptors. Macrophage inflammation activation and RPE cell pyroptosis are protective responses that resist local infection, which is consistent with previous findings that NLRP3-mediated inflammasome activation and IL-18 production prevent neovascularization of the retina.

[0035] Without being constrained by theory, the infectious etiology of AMD is consistent with the conclusions of all genetic studies. For example, defective CFH (a negative regulator of complement activation induced by Bacillus megatherium infection) leads to uncontrolled complement activation. Defective HTRA1 (a protease that produces the immunosuppressive cytokine TGF-β in an active form) leads to a decrease in local TGF-β family proteins. Both of these genetic mutations cause abnormal regulation of the local anti-infective response, damaging RPE cells and photoreceptors.

[0036] Furthermore, the potential differences in the pathogenic microbiome found in drusen can be interpreted as associations between different genetic risk factors and different ethnic groups (e.g., Caucasians and Asians). Therefore, there is evidence that the infectious etiology of AMD is the mechanism that causes early AMD pathology in older adults.

[0037] In short, in several embodiments, the inventors demonstrate that killing microorganisms and / or inhibiting their growth treats and / or prevents AMD, such as dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), such as dry or wet age-related macular degeneration with soft drusen symptoms.

[0038] Screening method The discovery that multiple types of intraocular diseases are associated with specific microorganisms also supports screening methods for candidate therapeutic agents to identify intraocular diseases, such as AMD. Therefore, some embodiments of the present invention relate to screening methods for multiple types of diseases. The screening methods of the present application may be in vitro methods (e.g., in a culture dish) or in vivo methods (e.g., using the animal models of the present application).

[0039] In some embodiments, the present invention provides a screening method comprising the steps of: a) culturing microorganisms in a suitable medium in the presence of a test compound; b) measuring the growth of microorganisms in the medium in the presence of the test compound; and c) optionally identifying candidate therapeutic agents that inhibit the growth of microorganisms compared to a control. Typically, the microorganisms include at least one species that are more concentrated in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of subjects with eye diseases than in healthy subjects, and the eye diseases are selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. In some embodiments, the method further comprises step d) determining, or having determined, one or more microbial species that are more concentrated in the intraocular space of subjects with eye diseases than in healthy subjects, the eye diseases being selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. In the method, healthy subjects used for comparison refer to subjects without eye diseases. The term “control” as used in the method is a placebo control that does not use the test compound. How to conduct an appropriate experiment for comparison will be obvious to those skilled in the art. In any of the embodiments of the present application, to the extent that it is not directly contradictory, the subjects may be human subjects. In any of the embodiments of the present application, to the extent that it is not directly contradictory, the screening method can be applied to identify candidate therapeutic agents for treating or preventing human diseases, such as the human eye diseases of the present application.

[0040] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of an eye disease, the method comprising the steps of: obtaining a sample taken from the aqueous humor or vitreous fluid of a subject selected from a subject suffering from the eye disease, a family member or close genetic relative of a subject suffering from the eye disease, or a deceased subject known to have the eye disease; culturing one or more organisms from the sample under conditions selected from conditions mimicking the intraocular space of a human eye or in cooked meat medium to produce one or more cultures; adding the compound or combination of compounds to the one or more cultures; and determining whether the compound or combination of compounds reduces the growth or population of the one or more cultures. In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro.

[0041] In some embodiments, family may include members of the subject's direct relatives, such as parents, children, or siblings. In some embodiments, family may include people who share living spaces with a subject who has an eye disease for an extended period. In some embodiments, close genetic relationships may include relationships of the subject who has the disease, which are within three direct generations of the subject's genetic relationships, such as the subject's great-grandparents, grandparents, parents, children, grandchildren / grandchildren, or great-grandchildren. In some embodiments, close genetic relationships may include the subject's siblings. In some embodiments, close genetic relationships may include relationships of the subject who has the disease, which are collateral relationships, including the subject's uncles, uncles, fathers-in-law, aunts-in-law, cousins, or nieces / nephews.

[0042] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of eye diseases, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas Maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbrickii, Meiothermus silvanu S(D), Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, Acidoborax ebreus, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus chrysoprase The method includes the steps of selecting from the group consisting of *Citrobacter thuringiensis*, *Citrobacter coseri*, *Diadobacter fermentans*, *Seratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium auricum*, *Finegordia magna*, and combinations thereof; adding the compound or combination of compounds to one or more cultures; and determining whether the compound or combination of compounds reduces the growth or population of the one or more cultures.In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro.

[0043] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of an eye disease, the method comprising the steps of: obtaining a sample taken from the aqueous humor or vitreous fluid of a subject selected from a subject suffering from the eye disease, a family member or close genetic relative of a subject suffering from the eye disease, or a deceased subject known to have the eye disease; culturing one or more organisms from the sample under conditions selected from conditions mimicking the intraocular space of a human eye or in cooked meat medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; mixing the compound or combination of compounds with the solution of the one or more inactivated proteins; and determining whether the compound or combination of compounds binds to the one or more inactivated proteins.

[0044] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment of an eye disease, the method comprising the steps of: obtaining a sample taken from the aqueous humor or vitreous fluid of a subject selected from a subject suffering from the eye disease, a family member or close genetic relative of a subject suffering from the eye disease, or a deceased subject known to have the eye disease; culturing one or more organisms from the sample under conditions selected from conditions mimicking the intraocular space of a human eye or in cooked meat medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; introducing the one or more inactivated proteins into a mammalian inflammation model; introducing the compound or combination of compounds into the mammalian inflammation model; and determining whether the compound or combination of compounds reduces inflammatory activity in the model.

[0045] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of eye diseases, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, and Batil. Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbrickii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococca *S. sedentarius*, *Alicyclifilus dennitrificans*, *Achromobacter xyloxidance*, *Sphingobium chaponicum*, *Mycobacterium auresus*, *Arthrobacter aurecens*, *Prevotella dentalis*, *Sinorhizobium melilotii*, *Acidovorax ebreus*, *Acinetobacter baumannii*, *Acinetobacter chalcoseticus*, *Comamonas testosterone*, *Mycobacterium kansasi*, *Bacillus thuringiensis*, *Citrobacter coseri*, *Diadobacter fermenta* The method includes the steps of selecting from the group consisting of Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finnegordia magna, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; mixing the compound or combination of compounds with the solution of the one or more inactivated proteins; and determining whether the compound or combination of compounds binds to the one or more inactivated proteins.In some embodiments, the method may further include the step of identifying a compound or combination of compounds that conjugate the one or more inactivated proteins in vitro, based on the determination result.

[0046] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of eye diseases, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbrickii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus cedentarius, Alisma Cliphyllus dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, The method includes the steps of selecting from the group consisting of Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finegordia magna, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; introducing the one or more inactivated proteins into a mammalian inflammation model; introducing the compound or combination of compounds into the mammalian inflammation model; and determining whether the compound or combination of compounds reduces inflammatory activity in the model.In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of one or more cultures in vitro. In some embodiments, the compound or combination of compounds may be one or more anti-inflammatory compounds.

[0047] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of an eye disease, the method comprising the steps of administering the compound or combination of compounds to the mammalian model of the present application and determining whether the compound or combination of compounds effectively reduces or prevents one or more symptoms of the eye disease. In some embodiments, the compound or combination of compounds is administered after a dorsenoid lesion has formed in the mammalian model. In some embodiments, the compound or combination of compounds is one or more compounds or combination of compounds identified by the in vitro screening method of the present application. In some embodiments, the injection may include an intraocular injection. In some embodiments, the one or more symptoms are selected from the group consisting of the development of a dorsenoid lesion, microbial growth or loading, the production of inflammatory molecules or markers and combinations thereof.

[0048] The microorganisms used in the above method may be substantially biologically pure species or multiple different species. In some embodiments, the microorganisms include at least one species that is the etiologist of an eye disease. In some embodiments, the microorganisms include at least one species, and killing or inhibiting the growth of the at least one species is beneficial for the treatment or prevention of the eye disease. Any techniques known in the art may be used for culturing the microorganisms and selecting the culture medium, and some exemplary details are shown in the Examples chapter. In some embodiments, the microorganisms may be cultured in liquid cooked meat medium. There are no particular limitations on the methods for measuring or determining the growth of the microorganisms, and any method generally known in the art is used, and some exemplary methods are described in the Examples chapter. To avoid doubt, quantitative measurement is not required in the measurement or determination of microbial growth. In some embodiments, for example, if the test compound prevents visible growth of the microorganisms below the maximum test concentration and / or prevents visible colonization of the microorganisms below the maximum test concentration, visual observation is sufficient.

[0049] Candidate therapeutic agents may be identified by any suitable technique known in the art. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing, for example, a corresponding eye disease if it inhibits microbial growth compared to a control at or below the maximum test concentration. In some embodiments, a test compound may be identified as a candidate therapeutic agent if it prevents visible growth of microorganisms at or below the maximum test concentration. In some embodiments, a test compound may be identified as a candidate therapeutic agent if it prevents visible colonization of microorganisms at or below the maximum test concentration.

[0050] The test compound can be tested at a single concentration or at multiple concentrations. In some embodiments, the minimum inhibitory concentration (MIC) of the corresponding test compound may be established, which allows for comparison between different test compounds and is advantageous for further identification / selection of candidate therapeutic agents.

[0051] Screening method for AMD In some specific embodiments, the screening method may be used to identify candidate therapeutic agents for treating or preventing AMD. In any of the foregoing embodiments of the Application, unless otherwise apparent in the context, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), e.g., dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method comprises the steps of a) culturing microorganisms in a suitable medium in the presence of a test compound, and b) measuring the growth of microorganisms in the medium in the presence of the test compound. Typically, the microorganisms include species that are more concentrated in the intraocular space of subjects with AMD (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens or iris) than in healthy subjects. For example, in some embodiments, the microorganisms include species that are concentrated in the aqueous humor, vitreous fluid, and / or soft drusen of subjects with AMD compared to healthy controls. In some embodiments, the microorganisms may include one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the microorganisms may include Bacillus megatherium and / or Pseudomonas putida. In some embodiments, the microorganisms include at least Bacillus megatherium. In some embodiments, the microorganisms may be a substantially biologically pure population of Bacillus megatherium.

[0052] The screening method of this application allows the use of microorganisms at various initial concentrations. For example, in some embodiments, the screening method of this application uses concentrations of approximately 10 μL (microliters) to approximately 500 μL (e.g., approximately 100 μL) and approximately 1*105 ~1×10 9 (For example, about 1×10 6 , about 1×10 8 or about 1×10 8 ) of Bacillus megaterium suspension can be placed in a petri dish containing about 10 - 15 mL of medium and incubated at an appropriate temperature and conditions, such as 37°C for 24 hours. For example, in some embodiments, for the screening method of the present application, about 1×10 5 ~1×10 9 (For example, about 1×10 5 or 1×10 7 ) of Bacillus megaterium can be used per culture.

[0053] In some embodiments, the microorganism may include a mixture of microorganism species, and the microorganism species are substantially similar to those observed in the aqueous humor, vitreous humor and / or soft drusen of a subject suffering from age-related macular degeneration. For example, in some embodiments, the pathogenic species identified in the aqueous humor, vitreous humor and / or soft drusen of a subject suffering from AMD may be included in the microorganism used in the screening method. The term "substantially similar" does not require that the microorganism has the same composition of microorganism species as those found in the aqueous humor, vitreous humor and / or soft drusen of a subject suffering from AMD. It is sufficient for the microorganism to contain most of the (preferably pathogenic) microorganism species that concentrate in the aqueous humor, vitreous humor and / or soft drusen of a subject suffering from AMD, as described in the present application for example. The term "substantially similar" used in combination with other eye diseases should be understood in the same way. In some embodiments, the microorganism may be partially or entirely derived from the aqueous humor and / or vitreous humor of a subject suffering from age-related macular degeneration. For example, in some embodiments, the microorganism can be obtained by culturing a sample taken from the aqueous humor and / or vitreous humor of a subject suffering from age-related macular degeneration. In some embodiments, if the test compound inhibits the growth of the microorganism (such as Bacillus megaterium) compared to the control, it can be identified as a candidate therapeutic agent for treating or preventing AMD.

[0054] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing AMD may further include the steps of: a) determining or having determined one or more microbial species that are concentrated in the intraocular space of subjects with age-related macular degeneration (AMD) compared to healthy subjects; b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control.

[0055] In some embodiments, the determination may involve obtaining information that one or more microbial species are more concentrated in the intraocular space of subjects with AMD than in healthy subjects. In some embodiments, the determination may involve evaluating the presence, absence, and / or quantity of microorganisms in a sample from the intraocular space of a subject with AMD, and optionally comparing the presence, absence, and / or quantity of such microorganisms with a healthy control. Methods for evaluating the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may include a mixture of microbial species, which are substantially similar to those observed in the aqueous humor, vitreous fluid, and / or soft drusen of subjects with age-related macular degeneration. In some embodiments, the microorganisms may be partially or entirely derived from the aqueous humor and / or vitreous fluid of a subject with age-related macular degeneration. For example, in some embodiments, microorganisms may be obtained by culturing samples taken from aqueous humor and / or vitreous fluid of subjects suffering from age-related macular degeneration. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing AMD if it inhibits microbial growth compared to a control.

[0056] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing AMD may further include the steps of: a) obtaining a sample from the intraocular space of a subject with AMD, e.g., aqueous humor, vitreous fluid, and / or soft drusen; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with AMD. In some embodiments, the sample is obtained from the vitreous fluid of a subject with AMD. In some embodiments, the sample is obtained from a soft drusen of a subject with AMD. As shown in the Examples chapter of this application, the incubation of the sample is usually carried out in a sterile culture medium in a sterile environment (e.g., a sealed environment) to avoid contamination with microbial species not initially present in the subject's sample. In some embodiments, a negative control may be used. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing AMD if it inhibits the growth of microorganisms in the culture medium compared to a control.

[0057] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of AMD, the method comprising the steps of: obtaining a sample taken from the aqueous humor or vitreous fluid of a subject selected from a subject with AMD, a family member or close genetic relative of a subject with AMD, or a deceased subject known to have AMD; culturing one or more organisms from the sample under conditions selected from conditions mimicking the intraocular space of a human eye or in cooked meat medium to produce one or more cultures; adding the compound or combination of compounds to the one or more cultures; and determining whether the compound or combination of compounds reduces the growth or population of the one or more cultures. In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro.

[0058] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment of an eye disease, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas marina Tofilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbrickii, Meiothermus sylvanus ( D) Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, Acidoborax ebreus, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus chu The method includes the steps of selecting a compound or combination thereof from the group consisting of -ingensis, citrobacter coseri, diadobacter fermentans, seratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricumosum, finegordia magna, and combinations thereof; adding the compound or combination of compounds to the one or more cultures; and determining whether the compound or combination of compounds reduces the growth or population of the one or more cultures.In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro.

[0059] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of AMD, the method comprising the steps of: obtaining a sample taken from aqueous humor or vitreous fluid of a subject selected from a subject with AMD, a family member or close genetic relative of a subject with AMD, or a deceased subject known to have AMD; culturing one or more organisms from the sample under conditions mimicking the human intraocular space or in cooked meat medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; mixing the compound or combination of compounds with the solution of the one or more inactivated proteins; and determining whether the compound or combination of compounds binds to the one or more inactivated proteins.

[0060] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of AMD, the method comprising the steps of: obtaining a sample taken from aqueous humor or vitreous fluid of a subject selected from a subject with AMD, a family member or close genetic relative of a subject with AMD, or a deceased subject known to have AMD; culturing one or more organisms from the sample under conditions selected from conditions mimicking the intraocular space of a human eye or in cooked meat medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; introducing the one or more inactivated proteins into a mammalian inflammation model; introducing the compound or combination of compounds into the mammalian inflammation model; and determining whether the compound or combination of compounds reduces inflammatory activity in the model.

[0061] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of eye diseases, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, and Batil. Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbrickii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococca *S. sedentarius*, *Alicyclifilus dennitrificans*, *Achromobacter xyloxidance*, *Sphingobium chaponicum*, *Mycobacterium auresus*, *Arthrobacter aurecens*, *Prevotella dentalis*, *Sinorhizobium melilotii*, *Acidovorax ebreus*, *Acinetobacter baumannii*, *Acinetobacter chalcoseticus*, *Comamonas testosterone*, *Mycobacterium kansasi*, *Bacillus thuringiensis*, *Citrobacter coseri*, *Diadobacter fermenta* The method includes the steps of selecting from the group consisting of Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finnegordia magna, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; mixing the compound or combination of compounds with the solution of the one or more inactivated proteins; and determining whether the compound or combination of compounds binds to the one or more inactivated proteins.In some embodiments, the method may further include the step of identifying a compound or combination of compounds that conjugate the one or more inactivated proteins in vitro, based on the determination result.

[0062] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment of eye diseases, the method comprising the step of culturing one or more organisms under conditions selected from conditions mimicking the intraocular space of the human eye or in cooked meat medium to produce one or more cultures, wherein the one or more organisms are Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus pallidum *Lactobacillus megatherium*, *Lactobacillus reuteri*, *Gardnerella vaginalis*, *Enterococcus faecium*, *Cytophaga hutchinsonii*, *Bacillus licheniformis*, *Xanthomonas oryzae*, *Sphingomonas witchii*, *Klebsiella pneumoniae*, *Pseudomonas fluorescein*, *Ralstonia picketti*, *Lactobacillus crispatus*, *Burkholderia multiboran*, *Lactobacillus delbruckii*, *Meiothermus sylvanus* (D), *Pseudomonas mendocina*, *Chitococcus cedentarius*, *Alicicli* Phyllus dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidobacter ebreus, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, M The method includes the steps of selecting from the group consisting of Icrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finegordia magna, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from one or more of the cultures; introducing the one or more inactivated proteins into a mammalian inflammation model; introducing the compound or combination of compounds into the mammalian inflammation model; and determining whether the compound or combination of compounds reduces inflammatory activity in the model.In some embodiments, the method may further include, based on the determination result, identifying a compound or combination of compounds that reduces the growth or population of one or more cultures in vitro. In some embodiments, the compound or combination of compounds may be one or more anti-inflammatory compounds.

[0063] In some embodiments, the present invention provides a method for screening the effectiveness of a compound or combination of compounds for the treatment of an eye disease, the method comprising the steps of administering the compound or combination of compounds to the mammalian model of the present application and determining whether the compound or combination of compounds effectively reduces or prevents one or more symptoms of AMD. In some embodiments, the compound or combination of compounds is administered after a dorsenoid lesion has formed in the mammalian model. In some embodiments, the compound or combination of compounds is one or more compounds or combination of compounds identified by the in vitro screening method of the present application. In some embodiments, the administration may include intraocular injection. In some embodiments, the one or more symptoms are selected from the group consisting of the development of a dorsenoid lesion, microbial growth or loading, the production of inflammatory molecules or markers and combinations thereof.

[0064] Screening methods for other diseases In some embodiments, the screening method may be used to identify candidate therapeutic agents for treating or preventing BD. In some embodiments, the method comprises the steps of a) culturing microorganisms in a suitable medium in the presence of a test compound, and b) measuring the growth of the microorganisms in the medium in the presence of the test compound, wherein the microorganisms include species that are concentrated in the intraocular space of subjects with BD (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) compared to healthy subjects. For example, in some embodiments, the microorganisms include species that are concentrated in the aqueous humor and / or vitreous fluid of subjects with BD compared to healthy controls. In some embodiments, the microorganisms may comprise one or more species selected from Sphingomonas witchii, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiborane, Lactobacillus delbruickii, and Meiothermus silvanus (D). In some embodiments, the microorganisms may comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from BD. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from BD. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from BD. In some embodiments, the test compound may be identified as a candidate therapeutic agent for treating or preventing BD if it inhibits microbial growth compared to a control.

[0065] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing BD may further include the steps of: a) determining or having determined one or more microbial species concentrated in the intraocular space of a subject with BD compared to a healthy subject; b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may involve obtaining information that one or more microbial species are concentrated in the intraocular space of a subject with BD compared to a healthy subject. In some embodiments, the determination may involve evaluating the presence, absence, and / or quantity of microorganisms in a sample from the intraocular space of a subject with BD, and optionally comparing the presence, absence, and / or quantity of the microorganisms with a healthy control. Methods for evaluating the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from BD. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from BD. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from BD. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing BD if it inhibits microbial growth compared to a control.

[0066] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing BD may further include the steps of: a) obtaining a sample from the intraocular space of a subject with BD, e.g., aqueous humor and / or vitreous fluid; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with BD. In some embodiments, the sample is obtained from the vitreous fluid of a subject with BD. As shown in the Examples chapter of this application, incubation of the sample is usually performed in a sterile culture medium in a sterile environment (e.g., a sealed environment) to avoid contamination with microbial species not present in the sample from the subject initially. In some embodiments, a negative control may be used. Therefore, if the test compound inhibits the growth of microorganisms in the culture medium compared to the control, it can be identified as a candidate therapeutic agent for treating or preventing BD.

[0067] In some embodiments, the screening method may be used to identify candidate therapeutic agents for treating or preventing cataracts. In some embodiments, the method comprises the steps of a) culturing microorganisms in a suitable medium in the presence of a test compound, and b) measuring the growth of the microorganisms in the medium in the presence of the test compound, wherein the microorganisms include species that are concentrated in the intraocular space of subjects with cataracts (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) compared to healthy subjects. For example, in some embodiments, the microorganisms include species that are concentrated in the aqueous humor and / or vitreous fluid of subjects with cataracts compared to healthy controls. In some embodiments, the microorganisms may comprise one or more species selected from Pseudomonas mendocina, Chitococcus sedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, and Acidoborax ebreus. In some embodiments, the microorganisms may comprise a mixture of microbial species that are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects with cataracts. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects with cataracts. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing cataracts if it inhibits microbial growth compared to a control.

[0068] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing cataracts may further include: step a) determining or having determined one or more microbial species concentrated in the intraocular space of a subject with cataracts compared to a healthy subject; step b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; step c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and step d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may involve obtaining information that one or more microbial species are concentrated in the intraocular space of a subject with cataracts compared to a healthy subject. In some embodiments, the determination may involve evaluating the presence, absence, and / or quantity of microorganisms in a sample from the intraocular space of a subject with cataracts, and optionally comparing the presence, absence, and / or quantity of the microorganisms with a healthy control. Methods for evaluating the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects with cataracts. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects with cataracts. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, the test compound may be identified as a candidate therapeutic agent for treating or preventing cataracts if it inhibits microbial growth compared to a control.

[0069] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing cataracts may further include the steps of: a) obtaining a sample from the intraocular space of a subject with cataracts, e.g., aqueous humor and / or vitreous fluid; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with cataracts. In some embodiments, the sample is obtained from the vitreous fluid of a subject with cataracts. As shown in the Examples chapter of this application, the incubation of the sample is usually carried out in a sterile culture medium in a sterile environment (e.g., a sealed environment) to avoid contamination with microbial species not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing cataracts if it inhibits the growth of microorganisms in the culture medium compared to a control.

[0070] In some embodiments, the screening method may be used to identify candidate therapeutic agents for treating or preventing GLA. In some embodiments, the method comprises the steps of a) culturing microorganisms in a suitable medium in the presence of a test compound, and b) measuring the growth of the microorganisms in the medium in the presence of the test compound, wherein the microorganisms include species that are concentrated in the intraocular space of subjects with GLA (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) compared to healthy subjects. For example, in some embodiments, the microorganisms include species that are concentrated in the aqueous humor and / or vitreous fluid of subjects with GLA compared to healthy controls. In some embodiments, the microorganisms may comprise one or more species selected from Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, and Serratia marcescens. In some embodiments, the microorganisms may comprise a mixture of microbial species that are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from GLA. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from GLA. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from GLA. In some embodiments, the test compound may be identified as a candidate therapeutic agent for treating or preventing GLA if it inhibits microbial growth compared to a control.

[0071] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing GLA may further include the steps of: a) determining or having determined one or more microbial species concentrated in the intraocular space of a subject with GLA compared to a healthy subject; b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may involve obtaining information that one or more microbial species are concentrated in the intraocular space of a subject with GLA compared to a healthy subject. In some embodiments, the determination may involve evaluating the presence, absence, and / or quantity of microorganisms in a sample from the intraocular space of a subject with GLA, and optionally comparing the presence, absence, and / or quantity of the microorganisms with a healthy control. Methods for evaluating the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from GLA. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from GLA. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from GLA. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing GLA if it inhibits microbial growth compared to a control.

[0072] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing GLA may further include the steps of: a) obtaining a sample from the intraocular space of a subject with GLA, e.g., aqueous humor and / or vitreous fluid; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with GLA. In some embodiments, the sample is obtained from the vitreous fluid of a subject with GLA. As shown in the Examples chapter of this application, the incubation of the sample is usually carried out in a sterile culture medium in a sterile environment (e.g., a sealed environment) to avoid contamination with microbial species not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing GLA if it inhibits the growth of microorganisms in the culture medium compared to a control.

[0073] In some embodiments, the screening method may be used to identify candidate therapeutic agents for treating or preventing vegetative keratitis (VKH). In some embodiments, the method comprises the steps of: a) culturing microorganisms in a suitable medium in the presence of a test compound; and b) measuring the growth of the microorganisms in the medium in the presence of the test compound, wherein the microorganisms include species that are concentrated in the intraocular space of subjects with VKH (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) compared to healthy subjects. For example, in some embodiments, the microorganisms include species that are concentrated in the aqueous humor and / or vitreous fluid of subjects with VKH compared to healthy controls. In some embodiments, the microorganisms include one or more species selected from Escherichia coli, Mycococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna. In some embodiments, the microorganisms may comprise a mixture of microbial species that are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from VKH. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from VKH. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from VKH. In some embodiments, the test compound may be identified as a candidate therapeutic agent for treating or preventing VKH if it inhibits microbial growth compared to a control.

[0074] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing VKH may further include the steps of: a) determining or having determined one or more microbial species concentrated in the intraocular space of a subject with VKH compared to a healthy subject; b) culturing microorganisms containing at least one of the concentrated microbial species in a suitable medium in the presence of a test compound; c) measuring the growth of the microorganisms in the medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may involve obtaining information that one or more microbial species are concentrated in the intraocular space of a subject with VKH compared to a healthy subject. In some embodiments, the determination may involve evaluating the presence, absence, and / or quantity of microorganisms in a sample from the intraocular space of a subject with VKH, and optionally comparing the presence, absence, and / or quantity of the microorganisms with a healthy control. Methods for evaluating the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects suffering from VKH. In some embodiments, the microorganisms may be derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from VKH. For example, in some embodiments, the microorganisms may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from VKH. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing VKH if it inhibits microbial growth compared to a control.

[0075] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing VKH may further include the steps of: a) obtaining a sample from the intraocular space of a subject suffering from VKH, e.g., aqueous humor and / or vitreous fluid; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and d) optionally identifying candidate therapeutic agents that inhibit the growth of microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject suffering from VKH. In some embodiments, the sample is obtained from the vitreous fluid of a subject suffering from VKH. As shown in the Examples chapter of this application, incubation of the sample is usually performed in a sterile culture medium in a sterile environment (e.g., a sealed environment) to avoid contamination with microbial species not present in the sample from the subject initially. In some embodiments, a negative control may be used. In some embodiments, a test compound may be identified as a candidate therapeutic agent for treating or preventing VKH if it inhibits the growth of microorganisms in the culture medium compared to a control.

[0076] Test compound There are no particular limitations on the test compounds used in the screening method of this application (for example, used to identify candidate therapeutic agents for treating or preventing AMD). For example, the test compounds may be small molecules, biological products (including polypeptides and polynucleotides), or conjugates of small molecules and biological products, such as antibody drug conjugates. Other suitable types of test compounds may also be used in the screening method of this application. The test compounds are not necessarily single compounds. In some cases, mixtures of compounds may be used for screening. For example, in some embodiments, extracts or fractions thereof, such as TCM extracts, can be used as test compounds for screening.

[0077] For example, the test compound may be a small molecule drug, a chemical drug, a large molecule drug, a biopharmaceutical, or a natural drug (traditional Chinese medicine or a traditional Chinese medicine extract). In some embodiments, the test compound may include a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or an azole antibiotic, or a combination thereof.

[0078] In some embodiments, the test compound is a β-lactam antibiotic, such as penicillins, cephalosporins, thienamicins, monobactams, β-lactamase inhibitors, methoxypenicillins, etc.; an aminoglycoside antibiotic, such as streptomycin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribomycin, micronomisomycin, azithromycin, etc.; a tetracycline antibiotic, such as tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; a chloramphenicol antibiotic, such as chloramphenicol, thianphenicol, etc.; a macrolide antibiotic, such as erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, medimycin, josamycin Antibiotics such as azithromycin; glycopeptide antibiotics, e.g., vancomycin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, e.g., norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin; nitroimidazole antibiotics, e.g., metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics, e.g., rifampicin; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; and other antibiotics, which may include one or more such as fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, etc.

[0079] In some embodiments, the test compound may include insect antimicrobial peptides, such as lepidopteran antimicrobial peptides, dipteran antimicrobial peptides, coleopteran antimicrobial peptides, damselfly antimicrobial peptides, hymenopteran antimicrobial peptides, silkworm antimicrobial peptides, etc.; mammalian antimicrobial peptides, such as porcine antimicrobial peptides, sheep antimicrobial peptides, bovine antimicrobial peptides, human antimicrobial peptides, etc.; amphibian antimicrobial peptides: such as African clawed frog; antimicrobial peptides derived from fish, mollusks, and crustaceans: such as sole (pardachirus pavoninus) antimicrobial peptides, catfish (parasilurus asotus) antimicrobial peptides, mussel antimicrobial peptides, shrimp antimicrobial peptides, etc.; plant antimicrobial peptides: such as thionin; and bacterial antimicrobial peptides: one or more of bacitracin, gramicidin, polymyxin, and nisin.

[0080] In some embodiments, the test compounds include Calcined ancient ink, Salvia Miltiorrhiza, Arnebia euchroma, Radix Isatidis, Houttuynia, Honeysuckle, Rhizoma Coptis, Scutellaria, Dandelion, Purslane, Hawthorn, Isatidis Folium, Fructus Forsythiae, Herba Artemisiae Capillaris, Andrographis Paniculata Nees, Radix Bupleuri, Rhubarb, and Euphorbia Humifusa), Stemonae, Garlic, Cortex Phellodendri, Eucommia, Cortex Fraxini, Fructus Cnidii, Galla Chinensis, Viola yedoensis makino, Fructus It may contain extracts or fractions of one or more of the following: Mume, licorice (Radix Glycyrrhizae), cinnamon bark (Pericarpium Granati), schisandra chinensis, cornflower (Spina Gleditsiae), oak (Terminalia Chebula), Sophora flavescens, cinnamon bark (Cortex Pseudolaricis), epimedium, and yolkflower (Artemisia apiacea Hance).

[0081] The screening method described above may be a low, medium, or high-throughput screening method, and can typically screen multiple test compounds. For example, in some embodiments, the screening method may screen one or more test compounds in parallel (including tests performed substantially simultaneously), for example, screening 10 or more, 100 or more, or 1000 or more compounds in parallel. The test compounds may be tested at a single concentration or at multiple concentrations. In some embodiments, when screening multiple test compounds, the multiple test compounds may include at least one test compound that is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. In some embodiments, the multiple test compounds may include at least one test compound that is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline. In some embodiments, the test compound is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. For example, in some embodiments, the test compound is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline.

[0082] In some embodiments, the test compound may include an anti-inflammatory compound. A suitable anti-inflammatory compound may include ophthalmic compounds known in the art. In some embodiments, the anti-inflammatory compound may include a steroid or nonsteroidal anti-inflammatory compound, a plant extract or extract fraction, or a combination thereof.

[0083] Animal models In some embodiments, the present invention further provides animal models for eye diseases and methods for producing such animal models.

[0084] In some embodiments, the present invention provides a method for preparing an animal model, the method comprising the step of introducing microorganisms and / or inactivated proteins derived from such microorganisms into the intraocular space of an animal's eye. Typically, the microorganisms include species that are more concentrated in the intraocular space of subjects with eye diseases than in healthy subjects (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris), the eye diseases are selected from cataracts (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), endophthalmitis (EOS), and combinations thereof, and the introduction induces one or more symptoms of the eye disease. In some embodiments, the method further includes determining, or having determined, one or more microbial species that are more concentrated in the intraocular space of subjects with eye diseases than in healthy subjects, the eye diseases being selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof.

[0085] In some embodiments, the method may introduce live microorganisms into the intraocular space of an animal's eye. In some embodiments, the method may introduce inactivated proteins from microorganisms, such as ultrasonically inactivated proteins from microorganisms, into the intraocular space of an animal's eye. The subjects and animals referred to in the methods of the present application may be the same or different. For example, in some embodiments, if the eye disease is a disease of a pet animal, the subjects and animals may be the same. In some embodiments, the eye disease may be a human disease, i.e., the subjects are human subjects and the animals are preferably non-human mammals, more preferably non-human primates (e.g., monkeys). In some embodiments, the animals have an anatomical structure and / or intraocular environment of the eye similar to that of a human. Preferably, the animals do not have an eye disease before the introduction of the microorganisms and / or inactivated proteins derived from the microorganisms.

[0086] AMD Animal Models In some specific embodiments, the present invention provides a method for preparing an animal model of AMD. In some embodiments, the method includes the step of introducing microorganisms and / or inactivated proteins derived from such microorganisms into the intraocular space of an animal's eye. Typically, the microorganisms include species that are more concentrated in the intraocular space of subjects with AMD than in healthy subjects (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris), and the introduction induces one or more symptoms of AMD. Unless otherwise stated in the context, the microorganisms introduced into the intraocular space of an animal are living microorganisms. In some embodiments, the microorganisms include one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the microorganisms include Bacillus megatherium and / or Pseudomonas putida. In some embodiments, the microorganisms include at least Bacillus megatherium. In some embodiments, the microorganisms are a substantially biologically pure population of Bacillus megatherium. In some embodiments, the microorganisms comprise a mixture of microbial species, which are substantially similar to those observed in the aqueous humor, vitreous fluid, and / or soft drusen of subjects suffering from age-related macular degeneration. In some embodiments, the microorganisms are derived in part or in whole from the aqueous humor and / or vitreous fluid of subjects suffering from age-related macular degeneration. For example, in some embodiments, the microorganisms can be obtained by culturing a sample obtained from the aqueous humor and / or vitreous fluid of a subject suffering from age-related macular degeneration. Preferably, the animal is a non-human mammal, more preferably a non-human primate (e.g., a monkey). In some embodiments, the animal has an anatomical structure of the eye and / or an intraocular environment similar to that of a human. In some embodiments, the animal is a rhesus macaque, e.g., a crab-eating macaque.In some embodiments, the animal is not a rhesus macaque. In some embodiments, the animal is not a crab-eating macaque.

[0087] Microorganisms and / or inactivated proteins derived from such microorganisms may be introduced into any suitable intraocular space of an animal. In some embodiments, microorganisms and / or inactivated proteins derived from such microorganisms are injected into the subretinal space of the animal. Typically, microorganisms and / or inactivated proteins derived from such microorganisms are injected into the eye of the animal, but other delivery methods are also appropriate.

[0088] Typically, microorganisms and / or inactivated proteins derived from such microorganisms are introduced in amounts and concentrations sufficient to induce one or more symptoms of AMD. For example, as shown in the Examples chapter, 20 CFU of bacteria in about 20 μL of PBS solution can induce one or more symptoms of AMD, such as dorsenoid lesions. In some embodiments, microorganisms and / or inactivated proteins derived from such microorganisms are introduced in amounts and concentrations sufficient to induce: 1) dorsenoid lesions in, for example, animal retinal tissue; 2) drusen-like nodules beneath the retinal pigment epithelium in, for example, animal eyes; 3) pyroptosis of retinal pigment epithelial cells in, for example, animal eyes; 4) activation and / or inflammation of the complement system in animal eyes, such as increased expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in, for example, animal eyes; or 6) any combination of 1)-5).

[0089] The animals used in the method for producing animal models of the present invention are preferably healthy animals, for example, that have no eye disease before the introduction of microorganisms and / or inactivated proteins derived from such microorganisms. Preferably, no antibiotics are administered to the animals before and during the introduction of microorganisms and / or proteins derived from such microorganisms, for example, before the appearance of one or more symptoms of AMD.

[0090] In some embodiments, a method for preparing an AMD animal model may include the step of introducing a sample from a subject suffering from AMD into the intraocular space of an animal's eye, the sample being obtained from the subject's intraocular space, and the introduction inducing one or more symptoms of AMD. In some embodiments, the sample is incubated in a culture medium and optionally purified and / or prepared for injection before introduction into an animal. In some embodiments, the method further includes the steps of 1) obtaining a sample from the subject's intraocular space, e.g., aqueous humor, vitreous fluid and / or soft drusen, and 2) incubating the sample in a culture medium. In some embodiments, the sample is obtained from the aqueous humor of a subject suffering from AMD. In some embodiments, the sample is obtained from the vitreous fluid of a subject suffering from AMD. In some embodiments, the sample is obtained from a soft drusen of a subject suffering from AMD. As shown in the Examples section of this application, the incubation of the sample is usually carried out in a sterile medium in a sterile environment (e.g., a sealed environment) to avoid introducing microbial species that are not present in the sample from the subject.

[0091] Typically, methods for creating AMD animal models can induce one or more AMD symptoms in animals that persist for a predetermined period of time. For example, without interference, animal models created by the present invention typically exhibit one or more AMD symptoms over a period longer than one week, one month, or throughout the animal's lifespan. Animal models created by the present invention are also a novel feature of embodiments of the present invention.

[0092] The AMD animal models prepared in this application can also be used to identify candidate therapeutic agents for treating or preventing AMD. For example, in some embodiments, the present invention further provides a screening method comprising the steps of: a) administering a comprehensive test compound to the AMD animal model of this application; b) determining the severity of one or more symptoms of the eye disease after administration; and c) optionally identifying candidate therapeutic agents that alleviate at least one of the symptoms compared to a control. In some embodiments, compared to a control, administration of the test compound may result in: 1) a reduction in dorsenoid lesions in, for example, retinal tissue of animals; 2) a reduction in drusen-like nodules beneath the retinal pigment epithelium layer in, for example, the eye of an animal; 3) a reduction in pyroptosis of retinal pigment epithelial cells in the eye of an animal; 4) a reduction in complement system activation and / or inflammation in the eye of an animal, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) a reduction in the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of an animal; or 6) any combination of 1)-5). Such test compounds may then be identified as candidate therapeutic agents for treating or preventing AMD. In some embodiments, compared to a control, administration of the test compound may kill or inhibit the growth of microorganisms in the eye (e.g., intraocular space or cavity), blood, and / or gastrointestinal tract, for example, the intestine, and such test compounds may also be identified as candidate therapeutic agents for treating or preventing AMD. In some embodiments, the relevant information for the "control" may be information observed in animals before administration of the test compound. In some embodiments, the relevant information for the "control" may be information observed in animals treated with a placebo, for example, by administering a placebo formulation that does not contain the test compound.

[0093] There are no limitations on the test compounds used in the screening method using an AMD animal model (as described herein), but preferably, the test compounds are pre-screened (for example, by any of the screening methods described herein) for their ability to effectively kill or inhibit the growth of microorganisms (e.g., Bacillus megatherium) that are concentrated in the intraocular space of subjects with AMD compared to healthy controls. The test compounds may be administered via any suitable route, in any drug delivery protocol or any suitable test dose, which may be selected by those skilled in the art on the basis of factors such as the potency of the test compound (if known). For example, the test compounds may be administered orally, topically, intravitreally, intramuscularly, subcutaneously or intravenously.

[0094] Screening methods using AMD animal models (as described herein) are typically low-to-medium throughput screening methods. In some embodiments, multiple test compounds are screened, and the multiple test compounds are at least one test compound that is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. In some embodiments, the multiple test compounds include at least one test compound that is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline. In some embodiments, the test compound is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. For example, in some embodiments, the test compound is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline.

[0095] In some embodiments, the present invention provides a method for preparing a mammalian model of an eye disease, the method comprising the step of preparing a mammalian model by introducing one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms into the eye of a mammal. In some embodiments, the method may further include the step of monitoring the onset and progression of one or more markers of the eye disease. The markers of the eye disease may include, but are not limited to, these biological and / or chemical markers for a given disease known in the art, and include, symptoms of the eye disease. In some embodiments, the step of monitoring the onset and progression of one or more markers of the eye disease may include monitoring the inflammatory response of the mammalian eye. In some embodiments, the step of monitoring the onset and progression of one or more markers of the eye disease may include monitoring the onset or progression of dorsenoid lesions. In some embodiments, the method further includes the step of allowing sufficient time to pass after the introduction of the one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms for the mammal to develop dorsenoid lesions. In some embodiments, the step of introducing one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms may include intraocular injection of the one or more microorganisms or one or more inactivated proteins of the one or more microorganisms. In some embodiments, the intraocular injection may include injection into the vitreous fluid or aqueous humor of a mammal.

[0096] Treatment method In some embodiments, the present invention further provides a method for treating or preventing AMD. In some embodiments, the method includes administering an effective dose of any candidate therapeutic agent for AMD identified by any screening method of the present application to a subject in need thereof. In some embodiments, the method includes identifying, or having identified, that a subject is infected in the intraocular space with one or more species selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering to the subject an effective dose of any candidate therapeutic agent for AMD identified by any of the screening methods of the present invention. In some embodiments, the method includes the steps of comprehensively identifying or identifying a subject who is infected, for example, in the intraocular space with Bacillus megatherium and / or Pseudomonas ptyda, preferably at least Bacillus megatherium, and administering to the subject an effective dose of any candidate therapeutic agent for AMD identified by any of the screening methods of the present application. In some embodiments, the method includes the steps of selecting a subject infected in the intraocular space with one or more species selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering an effective dose to the subject of any candidate therapeutic agent for AMD identified by any of the screening methods of the present invention.In some embodiments, the method includes the steps of selecting a subject infected, for example, in the intraocular space with Bacillus megatherium and / or Pseudomonas ptida, preferably at least Bacillus megatherium, and administering to the subject an effective dose of any candidate therapeutic agent for AMD identified by any of the screening methods of the present application. In some embodiments, the subject does not have Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the subject has AMD. In some embodiments, the subject has not been diagnosed with AMD. In some embodiments, the subject is at risk of developing AMD. Administration is not limited to any particular route and may be, for example, oral, topical, intravitreal, intramuscular, subcutaneous, and / or intravenous.

[0097] In some embodiments, a method for treating or preventing AMD includes the steps of identifying, or having identified, that a subject is infected in the intraocular space with one or more species selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering an effective dose of an antibiotic to the subject. The term "antibiotic" as used in this application generally refers to a compound having antibacterial activity, which may be naturally occurring or synthesized. Several antibiotics are listed in this application. In some embodiments, the method includes the steps of identifying, or having identified, that a subject is infected, for example, in the intraocular space with Bacillus megatherium and / or Pseudomonas putida, preferably at least Bacillus megatherium, and administering an effective dose of antibiotics to the subject. In some embodiments, the method includes the steps of selecting a subject who is infected, for example, in the intraocular space with one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering an effective dose of antibiotics to the subject. In some embodiments, the method includes the steps of selecting a subject who is infected with, for example, Bacillus megatherium and / or Pseudomonas putida, preferably at least Bacillus megatherium, in the intraocular space, and administering an effective dose of antibiotics to the subject.In some embodiments, the subject does not have Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the subject has AMD. In some embodiments, the subject has not been diagnosed with AMD. In some embodiments, the subject is at risk of developing AMD. Administration is not limited to any particular route, and may be, for example, oral, topical, intravitreous, intramuscular, subcutaneous, and / or intravenous. In any embodiment of the present application, the “effective dose” of the antibiotic may be an amount that effectively kills or inhibits the growth of one or more microbial species in the eye of the subject being treated, and such one or more microbial species are concentrated in AMD patients compared to healthy controls, and such one or more microbial species may be, for example, Bacillus megatherium and / or Pseudomonas putida, preferably at least Bacillus megatherium.

[0098] In some embodiments, the present invention further provides a method for achieving the following in subjects who require it: 1) reducing dorsenoid lesions in retinal tissue, for example; 2) reducing drusen-like nodules beneath the retinal pigment epithelium in the eye, for example; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing complement system activation and / or inflammation in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5). The method comprises administering to a subject an effective dose of any candidate therapeutic agent for AMD identified by any screening method of the present application. In some embodiments, the present invention further provides a method for treating drusen symptoms (e.g., soft drusen) in subjects who require it, the method comprising administering to a subject an effective dose of any candidate therapeutic agent for AMD identified by any screening method of the present application. Drusen symptoms (e.g., soft drusen) may be induced by microbial infection, such as the pathogenic bacteria described herein. Drusen symptoms (e.g., soft drusen) may also be associated with subjects suffering from AMD.

[0099] In some embodiments, the present invention further provides a method for achieving the following in subjects who require it: 1) reducing dorsenoid lesions in, for example, retinal tissue; 2) reducing drusen-like nodules beneath the retinal pigment epithelium layer in the eye; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing complement system activation and / or inflammation in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5). The method comprises the step of administering an effective dose of an antibiotic to the subject. For example, in some embodiments, the method reduces dorsenoid lesions in the subject. In some embodiments, the method reduces drusen-like nodules in the subject. In some embodiments, the method reduces pyroptosis of retinal pigment epithelial cells in the subject's eye. In some embodiments, the method reduces complement system activation and / or inflammation in the subject's eye. In some embodiments, the method reduces the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the subject's eye. Without wishing to be constrained by theory, it is conceivable that antibiotics may kill or inhibit the growth of bacteria (e.g., pathogenic bacteria) in the subject's intraocular space, thereby reducing drusen formation, dorsenoid lesions and / or drusen-like nodules in subjects suffering from AMD, as is evident from this application, AMD is associated with infection by one or more pathogenic microorganisms (e.g., Bacillus megatherium and / or Pseudomonas putida). Furthermore, it is conceivable that pathogenic microorganisms, such as those described in this application, such as Bacillus megatherium and / or Pseudomonas putida, can induce inflammation of the eye. Therefore, antibiotics that can kill or inhibit the growth of administered pathogenic microorganisms may also reduce ocular inflammation in subjects (e.g., subjects suffering from AMD).In some embodiments, the present invention further provides a method for treating drusen symptoms (e.g., soft drusen) in a subject in need thereof, the method comprising the step of administering an effective dose of an antibiotic to the subject. Drusen symptoms (e.g., soft drusen) may be induced by a microbial infection, such as the pathogenic bacteria of the present application. Drusen symptoms (e.g., soft drusen) may be associated with a subject suffering from AMD. In some embodiments, the method reduces dorsenoid lesions and / or nodules.

[0100] In some embodiments, the present invention further provides methods for achieving the following in subjects requiring it: 1) reducing dorsenoid lesions in retinal tissue, for example; 2) reducing drusen-like nodules beneath the retinal pigment epithelium layer in the eye, for example; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing complement system activation and / or inflammation in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5). The method comprises the step of administering to a subject an effective amount of one of the compounds of the Disclosure (e.g., compounds of formula I (e.g., formula I-1, formula I-2, formula I-3, formula I-4, formula I-5), formula II (e.g., formula II-1, formula II-2, formula II-3, formula II-4, formula II-5, formula II-6, formula II-7, formula II-8, formula II-9, formula II-10), formula III (e.g., formula III-1, formula III-2, formula III-3), formula IV-1 or IV-2 (e.g., formula IV-3, formula IV-4, formula IV-5, formula IV-6), a glycoside (e.g., formula V), a compound selected from compounds 1 to 8, or a pharmaceutically acceptable salt or ester, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt or ester, where the aglycone of the glycoside is a phenol compound, a flavonoid, a coumarin, a benzoic acid, or a sterol). For example, in some embodiments, the method is for reducing dorsenoid lesions in a subject. In some embodiments, the method reduces drusen-like nodules in a subject. In some embodiments, the method reduces pyroptosis of retinal pigment epithelial cells in the subject's eye. In some embodiments, the method reduces complement system activation and / or inflammation in the subject's eye. In some embodiments, the method reduces the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the subject's eye.Without being constrained by theory, it is conceivable that the compounds of this disclosure may, for example, kill or inhibit the growth of bacteria (e.g., pathogenic bacteria) in the intraocular space of a subject, thereby reducing drusen formation, dorsenoid lesions and / or drusen-like nodules in a subject suffering from, for example, AMD, as is evident from this application, AMD is associated with infection by one or more pathogenic microorganisms (e.g., Bacillus megatherium and / or Pseudomonas putida). Furthermore, it is conceivable that pathogenic microorganisms, such as those described in this application, such as Bacillus megatherium and / or Pseudomonas putida, can induce inflammation of the eye. Therefore, compounds of this disclosure that kill or inhibit the growth of administered pathogenic microorganisms may also reduce ocular inflammation in a subject (e.g., a subject suffering from AMD). In some embodiments, the present invention further provides a method for treating drusen symptoms (e.g., soft drusen) in subjects in need thereof, the method comprising the step of administering an effective amount of the compounds of the present disclosure to the subject. Drusen symptoms (e.g., soft drusen) may be induced by a microbial infection, e.g., the pathogenic bacteria of the present application. Drusen symptoms (e.g., soft drusen) may be associated with subjects suffering from AMD. In some embodiments, the method reduces dorsenoid lesions and / or nodules.

[0101] There are no particular limitations on the subjects suitable for treatment by the method of this application. In some preferred embodiments, the subject has AMD. In some embodiments, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), for example, dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject has soft drusen deposition between the retinal pigment epithelium (RPE) and Bruch's membrane. In some embodiments, the subject has retinal pigment changes in the macula. In some embodiments, the subject has dry AMD. In some embodiments, the subject has wet AMD. In some embodiments, the subject is a human subject. In some embodiments, the subject is infected in the intraocular space with one or more species that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described above. In some embodiments, the subject is infected in the intraocular space with one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the subject is infected with Bacillus megatherium and / or Pseudomonas ptida, preferably at least Bacillus megatherium, in the intraocular space. In some embodiments, the subject does not have Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof.In some embodiments, the method may further include identifying, or having identified, that the subject is infected in the intraocular space with one or more species that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described above. In some embodiments, the method may further include identifying, or having identified, that the subject is infected in the intraocular space with one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the method may further include identifying, or having identified, that the subject is infected with Bacillus megatherium and / or Pseudomonas putida, preferably at least Bacillus megatherium, in the intraocular space.

[0102] The administration of antibiotics is not limited to any particular route of administration. For example, administration may be oral, topical, intravitreous, intramuscular, subcutaneous, and / or intravenous. For example, in some embodiments, antibiotics are administered by intravitreous injection, e.g., intravitreous depot injection or intravitreous implantation. In some embodiments, combinations of two or more routes of administration (e.g., oral and intravitreous routes) are available. For example, in some embodiments, antibiotics may be administered orally and intravitreously simultaneously or sequentially in any order. For example, in some embodiments, antibiotics may be administered orally and intravenously simultaneously or sequentially in any order. In the case of the same active ingredient or two different active ingredients, they may be used in combination with other routes of administration. Antibiotics may be prepared in solid, liquid, semi-solid, solution, suspension, implant, or any other suitable form. For example, oral antibiotics are usually in solid or liquid form. In some embodiments, antibiotics may be prepared as implants. In the case of intravitreous injection, there are no particular restrictions on the injection site. For example, in some embodiments, the injection may be a suprachoroidal injection. Other suitable sites are known in the art. The effective dose can vary depending on several factors, such as administration time, route of administration, duration of treatment, antibiotic efficacy (e.g., killing or inhibiting the growth of one or more microorganisms concentrated in the intraocular space compared to a healthy control), clearance, and whether another drug is administered simultaneously. Several antibiotics, such as any one of these antibiotics described in this application and any one of the antibiotics described in PCT / CN2019 / 070572 filed on January 7, 2019, may be used in the method of this application, and the content of that patent as a whole is incorporated into this application by reference.

[0103] In some embodiments, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or an azole antibiotic, or a combination thereof.

[0104] In some embodiments, the antibiotic is a β-lactam antibiotic, such as penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pivampicillin, pibmecillinum, ticarcillin, cephalosporins such as cephastril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapirin, ceph Atrazine, Cefazalur, Cefazedone, Cefazolin, Cepharazine, Cefuroxazine, Ceftezol, Cefaclor, Cephamandol, Cefmetazole, Cefonisid, Cefotetan, Cefoxitin, Cefprodil, Cefuroxime, Cefzonam, Cefcapene, Cefdaroxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefozidime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Cefthioflu, Cephthaloline, Ceftizoxime, Ceftriaxone, Cefope Lazon, ceftazidime, cefclizine, cefepime, ceffluprenum, cefoselis, cefozopran, cefpirome, cefquinome, ceftoviprole, cephthaloline, cefaclomedine, cephaloram, cephaparol, cefcanel, cefedrol, cefenpidone, cefetrizole, cefibitril, cefmatilen, cefmepidium, cefobesin, cefoxazole, cefrotil, cefsumide, cefuratime, ceftioxide, thienamicin derivatives, monobactam derivatives, β-lactamers Ze inhibitors, methoxypenicillins; aminoglycoside antibiotics, such as streptomycin, gentamicin, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribomycin, micronomisomycin, azithromycin, dibekacin, shisomycin, netylmycin, paromomycin, bramycin, etc.; tetracycline antibiotics, such as tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.Chloramphenicol antibiotics, e.g., chloramphenicol, thianphenicol, etc.; macrolide antibiotics, e.g., erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, medimycin, josamycin, azithromycin, clarithromycin, dilithromycin, roxithromycin, telithromycin, etc.; glycopeptide antibiotics, e.g., vancomycin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, e.g., norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin ; Nitroimidazole antibiotics, e.g., metronidazole, tinidazole, ornidazole; Rifamycin antibiotics, e.g., rifampicin; Echinocandin antibiotics; Polyene antibiotics; Pyrimidine antibiotics; Allylamine antibiotics; Azole antibiotics; Other antibiotics: May include one or more of the following: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, and polymyxin B combinations, e.g., polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / gramicidin.

[0105] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, salvarsan, azithromycin, azurocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cephalothin, cephamandol, cefazolin, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprodil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, ceffuroxime, chloramphenicol, Cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dalfopristin, dapsone, daptomycin, dicloxacillin, zilithromycin, doripenem, doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, loracalbef, mafenide, meropenem, methoxypenicillin, metronidazole Zole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netylmycin, nitrofurantoin, oxacillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifamycin, rifapentin, rifaximin, roxithromycin, silver sulfadiazine, spectinomycin, streptomycin, sulba Tam, sulfacetamide, sulfadiazine, sulfamethizol, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavancin, telithromycin, temocillin, tetracycline, thianphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, trimethoprim, troreoandmycin, vancomycin, enoxacin, lomefloxacin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin,Moxifloxacin, ofloxacin, norfloxacin, cefotetan, cefonisid, cephaladine, cefapillin, cephalothin, cefmetazole, cefotaxime, moxalactam, cefepime, cephthaloline fosamil, ceftoviprole, dalbavancin, demeclocycline, metacycline, ertapenem, fidaxomicin, geldanamycin, harbimycin, posizolid, radezolid, Torezolid, Oritavancin, Spiramycin, Sulfadimethoxine, Sulfonamidochrysoidine, Gemifloxacin, Nadifloxacin, Trovafloxacin, Glepafloxacin, Sparfloxacin, Temafloxacin, Teixobactin, Malacidins, and combinations thereof may be selected.

[0106] In some embodiments, the present invention further provides candidate therapeutic agents identified by any of the screening methods of this application, or pharmaceutical compositions comprising such candidate therapeutic agents, for treating or preventing AMD.

[0107] compound In some embodiments, the present disclosure relates to a plurality of compounds and / or compositions comprising such compounds that can kill or inhibit the growth of microorganisms associated with AMD, such as Bacillus megatherium.

[0108] The compounds of this application typically have antimicrobial activity on their own or in combination with other agents. The compounds of this application may be bactericidal or bacteriostatic. Multiple compounds known to have antimicrobial activity may be used in embodiments of the present invention. For example, in some embodiments, the compounds of this application may include any alcohols, phenolic compounds, amines, sulfonamides, quinolones, anthraquinones and / or related compounds of benzoic acid known to have antimicrobial activity. Limited examples of useful compounds include benzoic acid, benzyl alcohol, coumarins, catechols, polyphenols, chalconoids (including licochalcones), stilbenes such as resveratrol and isoresveratrol, phenolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acid, caffeic acid, ferulic acid, chlorogenic acid, sinapic acid, flavonoids such as catechin, naringenin, quercetin, rutin, and chrysin, tannins such as ellagic acid, and their esters and glycosides.

[0109] The characteristic features of the compounds of this application are typically certain functional groups present in their molecular structure. For example, in some embodiments, the characteristic features of the compounds of this application are having an alcoholic hydroxyl group, a phenolic hydroxyl group and / or a carboxylic acid group or derivatives thereof, such as esters, amides, carbonate esters, carbamates, sulfonic acid esters, glycosides, etc. In some embodiments, compounds having an amino group, a sulfonamide group, a thiol group and / or a sulfoxide group or a sulfone group can also be used in the compositions and methods of this application.

[0110] The compounds of the present application may have a polycyclic core structure, a bicyclic core structure, or a monocyclic core structure, and any of these may be substituted with the aforementioned multiple groups.

[0111] In some embodiments, the compounds of the present application may be characterized by having formula I or a pharmaceutically acceptable salt or ester. JPEG2026086398000002.jpg4159. To avoid any ambiguity, let me clarify that in formula I, the cyclic structure Cy 1 and another cyclic structure Cy 2 This consists of two ringers L and L ’ They are connected via, and these two ring structures may be the same or different, and these two ringers are Cy 1 and Cy 2 It forms another ring structure between them. 1 and Cy 2 These are L and L respectively. ’ It is a ring structure independent of the others. In formula I, Cy 1 and Cy 2 Each of these is independently a substituted cycloalkyl ring (e.g., C 3-7 Cycloalkyl rings), substituted heterocycles, for example, substituted 4-7 membered heterocycles (e.g., having one or two cycloheteratoms independently selected from N, O, and S), substituted aromatic rings (e.g., C 6-10 Aromatic rings (e.g., phenyl groups) or substituted heteroaromatic rings, for example, substituted 5-10 membered heteroaromatic rings (e.g., 5 or 6 membered heteroaromatic rings having one or two cycloheteroatoms independently selected from N, O, and S), L and L ’ Each of these can be independently empty or ringer (e.g., as described herein), and as used herein, the term “ringer” is not limited to any particular type of linking group. For example, in some embodiments, a ringer may form a ring structure with the one portion to which it is bonded, for example, L and Cy 1 is Cy 2 They may form a ring structure independently of each other. L 2 C may be empty or substituted. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C3-6 This may be a cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group. W is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or The file is JPEG2026086398000003.jpg1818, Here, R 1 and R 1a Each of these is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group. R 3 and R 4 These are, independently, hydrogen and -COR 2b , -SO2R 5b , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 3 and R 4 These, together with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group. R2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , optionally substituted C 1-6 alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 alkoxy group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 3-6 cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7-membered heterocyclic group, and R 3a , R 3b , R 3c , R 3d , R<{, R 4a , R 4b , R 4c , R<{and R<000008%are each independently hydrogen, optionally substituted C 1-6 alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 alkoxy group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 3-6 cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7-membered heterocyclic group, or R 3a [[ID=6{ and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d or R 3e and R 4e together with the atom to which they are attached form an optionally substituted 4-7-membered heterocyclic group. Cy in equation I 1 and Cy 2 Cy in formula I may be an aromatic or non-aromatic ring system and may optionally contain heteroatoms. In a preferred embodiment, Cy 1 and Cy 2 At least one of them is an aryl group or a heteroaromatic ring, for example, a substituted C 6-10 The aromatic ring, or a substituted 5-10 member heteroaromatic ring. For example, in some embodiments, Cy 1 and Cy 2 This does not show any substituents that form the core structure of formula I. The structure of JPEG2026086398000004.jpg1822 may be either one of the following: JPEG2026086398000005.jpg78122, here, L 2 -W may be connected to the left ring or the right ring, where L and L ’ This may be any one of the above-mentioned features of the present application, and suitable substituents for use in the ring are described in the present application.

[0112] In some embodiments, Cy in formula I 1 and Cy 2 Each of these may be an aryl group or a heteroaromatic ring. For example, in some embodiments, the compound of formula I may have formula I-1. JPEG2026086398000006.jpg4558.

[0113] In some embodiments, Ar in formula I-1 1 and Ar 2 Each of these can be substituted independently of C. 6-10 The aromatic ring, or a substituted 5-10 member heteroaromatic ring. In some embodiments, the Ar in formula I-1 1 and Ar 2 Each of these is independently a substituted benzene ring or a 5- or 6-membered heteroaromatic ring. For example, in some embodiments, Ar in formula I-1 1 and Ar 2Each of these is independently a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring. Formula I-1 typically has a polycyclic core structure. For example, in some embodiments, Ar 1 and Ar 2 This does not show any substituents that form the core structure of formula I-1. Ensure that JPEG2026086398000007.jpg1822 can be any one of the following: JPEG2026086398000008.jpg92170, here, L 2 -W may be connected to the left ring or the right ring, where L and L ’ This is defined in this application, and suitable substituents for use in the ring are described therein.

[0114] In some embodiments, the compound of formula I may have formula I-2. JPEG2026086398000009.jpg3058, During the ceremony, m is 0, 1, 2, or 3. R 10 Each time it appears, it independently emits halogen, L 2’ -W ’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 10 , or one R 10 and L or L ’ These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. Here, -L2’ -W ’ Each time it appears, it is independently chosen, and L 2’ Each time it appears, it may be replaced by an empty C independently. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group, and W ’ Each time it appears, independently, -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or The file is JPEG2026086398000010.jpg1818, and here, R 1 , R 1a , R 2 , R 2a , R 2b , R 3 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 5a and R 5bThis is defined in this application, see, for example, formula I. Note: Structural unit -L 2’ -W ’ and -L 2 Each instance of -W is chosen independently and may be identical or different.

[0115] In some embodiments, Cy in formula I-2 1 is a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring. In some embodiments, Cy in formula I-2 1 C may be substituted. 3-6 The heterocycle is a cycloalkyl ring or a substituted 4-7 heterocycle, the heterocycle having one or two cycloheteroatoms independently selected from N, O, and S.

[0116] In some embodiments, Cy 1 This ensures that the core structure of equation I-2 may be any one of the following: JPEG2026086398000011.jpg32116 Here, -L 2 -W is connected to the benzene ring on the right side, and L and L ’ This is defined in this application, and suitable substituents for use in the ring are described therein.

[0117] In a more preferred embodiment, Cy in formula I 1 and Cy 2 These are all benzene rings. For example, in some embodiments, the compound of formula I-2 may have formula I-3. JPEG2026086398000012.jpg2676, During the ceremony, L, L ’ , L 2 , W, R 10 And m are defined herein, see, for example, formula I-2, where n is 0, 1, 2, or 3. R 11 Each time it appears, it independently emits halogen, -L 2’ -W’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 11 , or one R 11 and L or L ’ These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring, where L 2’ and W ’ This is defined in this application, see, for example, the definition in formula I-2, and -L 2’ -W ’ Each time they appear, they are chosen independently. L and L in equation I (for example, any one of equations I-1 to I-3) ’ These may be empty or ringer independently. In some embodiments, L and L in formula I ’ These are, independently, empty, -C(O)-, and C which may be substituted. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, -O-, -S-, -NR 100 -, -S(O)-, -SO2-, -X 1 -G 1 -, -X 2 -G 2 -X 2a - or -CR 101 R 102 -and here, X 1 , X 2 and X 2a C may be substituted independently. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, -O-, -C(O)-, -S-, -NR 100a-, -S(O)-, -SO2-, or -CR 101a R 102a -and, G 1 and G 2 C may be substituted independently. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, -C(O)-, -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, Preferably, in some embodiments, -X 1 -G 1 - or -X 2 -G 2 -X 2a - does not contain ON, SS, SN (excluding SO2-N), or -C(O)-S bonds. R 100 and R 100a These are, independently, lone pairs of electrons (if applicable), hydrogen, and COR 2c , -SO2R 5c , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 100 or R 100a is R 10 or R 11 Forms a heterocycle or heteroaromatic ring which may be substituted with a group, R 101 , R 101a , R 102 and R 102a If present, each can independently be hydrogen, -OH, halogen, or substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 Cycloalkyl groups, may be substituted C 1-6Alkoxy group, substituted KarC 3-6 A cycloalkoxy group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group, or R 101 and R 102 , or R 101a and R 102a These, together with the atoms to which they are bonded, form a substituted 3-7 membered cycloalkyl or heterocyclyl ring, or R 101 and R 102 One of the two, or R 101a and R 102a One of them is R 10 or R 11 Together with the group, it forms a substituted cycloalkyl group or heterocyclyl ring, and R 2c and R 5c These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 The group is a cycloalkoxy group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- to 7-membered heterocyclic group. Ringer L or L ’ If it forms a double bond with one of the ring carbons, then this is R 101 and R 102 CR 101 R 102 This is not the case, because the valence of carbon exceeds 4. In such cases, R 101 and R 102 One of them does not exist, and L or L ’ This is the CR as defined in this application. 101 or CR 102 It is L or L ’ If it forms a double bond with one of the ring carbons, this is NR 100 It may also be the case that R100 These are typically lone pairs of electrons. Other similar situations in this disclosure should be understood in the same way.

[0118] In some embodiments, L and L in formula I ’ These are, independently, empty, -O-, -C(O)-, -S-, and -NR. 100 -, -S(O)-, -SO2-, or -CR 101 R 102 -In some embodiments, the compound of formula I has a formula consisting of one of I-4 to I-5. JPEG2026086398000013.jpg5295 and JPEG2026086398000014.jpg5198In formula, X 3 , X 4 and X 5 These are, independently, empty, -O-, -C(O)-, -S-, and -NR. 100a -, -S(O)-, -SO2-, or -CR 101a R 102a - and R 10 , R 11 , R 100a , R 101a , R 102a W, L 2 m and n are defined in this application.

[0119] In some embodiments, the compound has formula I-4, where X 3 and X 4 These are -O-, -C(O)-, -S-, and -NR, respectively, and are independent of each other. 100a - or -SO2-. In some embodiments, the compound has formula I-5, where X 5 -O-, -C(O)-, -S-, -NR 100a - or -SO2-. In some embodiments, R 100a C is hydrogen or may be substituted. 1-4 It is an alkyl group. In formula I (for example, any of the aforementioned sub-formulas of this application, e.g., formulas I-1 to I-5), L 2It is usually empty, that is, the W group is Cy 2 It is directly connected. In some embodiments, L in formula I 2 C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It may also be a heteroalkylene group. For example, the W group is connected to Cy via a methylene group or an ethenyl group. 2 It may also be connected to it. Multiple types of W groups are suitable for compounds of formula I (for example, any of the sub-formulas of this application, e.g., formulas I-1 to I-5). In preferred embodiments, each W group is independently -OH, -NH2, -SO2NH2, -SO2NH(C) 1-4 Alkyl), -SO2NH(C 1-4 Alkanoyl), -COOH, JPEG2026086398000015.jpg1818, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 Alkyl) and here each C 1-4 Alkyl groups are independently C 1-4 Alkyl alkyl group, C 1-4 The substituents may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, W in formula I is -OH, -NH2, -SO2NH2, -SO2NH(acetyl), -COOH, The filename is JPEG2026086398000016.jpg1818 or -OC(O)-CH3. As described in this application, L 2’ -W ’ In some embodiments, Cy 1 or Cy 2 For example, Ar 1 Or Ar 2The substituent may be selected for use in the following case: 2’ Each time it appears, for example, Ar 1 Or Ar 2 (If applicable) it may be empty independently, i.e., W ’ The base is Cy 1 or Cy 2 Directly connected to, or C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It is a heteroalkylene group. For example, W ’ The base is, for example, Ar 1 Or Ar 2 Regarding this, via a methylene group or an ethenyl group, Cy 1 or Cy 2 It may be connected to. If applicable, W in formula I (including any of the aforementioned subformulas of this application, e.g., formulas I-1 to I-5) ’ Each time it appears, it independently produces -OH and -NH. 2 -SO2NH2, -SO2NH(C 1-4 Alkyl), -SO2NH(C 1-4 Alkanoyl), -COOH, JPEG2026086398000017.jpg1818, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 It may also be alkyl, where each C 1-4 Alkyl groups are independently C 1-4 Alkyl alkyl group, C 1-4 It may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, when applied, W in formula I ’ Each instance of -OH, -NH2, -SO2NH2, -SO2NH(acetyl), -COOH, The filename may be JPEG2026086398000018.jpg1818 or -OC(O)-CH3. Multiple types of bases are R in any applicable formula I (for example, any of the aforementioned sub-formulas of this application, e.g., formulas I-2 to I-5, if applicable). 10 and R 11 Applicable to some embodiments, R 10 and R 11 Each of these, whenever it appears, independently, F;Cl;-OH;-NH2;-SO2NH2;-SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl);-COOH; JPEG2026086398000019.jpg1818;-C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl), C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 Alkyl alkyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkenyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkynyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkoxy group; or C 1-4 Alkyl alkyl group, C 1-4C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 It may be an alkoxy group. In some embodiments, R 10 and R 11 Each of these, whenever it appears, independently, -OH;-NH2;-SO2NH2;-SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl);-COOH; JPEG2026086398000020.jpg1818;-C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl); C 1-4 Alkyl alkyl group; or C 1-4 It may be an alkoxy group. In some embodiments, R 10 One or more instances of and / or R 11 One or more instances of the L described herein are independently L as described herein. 2’ -W ’ It may be selected from among them. Typically, m is 0, 1, or 2, preferably 1, when applicable. Typically, n is 0, 1, 2, or 3, preferably 1 or 2, when applicable.

[0120] In some embodiments, the compounds of the present application may be characterized by salts or esters having formula II or pharmaceutically acceptable salts or esters. JPEG2026086398000021.jpg2184, During the ceremony, Cy 10 and Cy 11 Each of these is independently a substituted cycloalkyl ring (e.g., C 3-7 Cycloalkyl rings), substituted heterocycles (e.g., 4-7 membered heterocycles), substituted aromatic rings (e.g., C 6-10Aromatic ring), a substituted heteroaromatic ring (e.g., a 5-10 membered heteroaromatic ring), or a substituted ring structure comprising a cycloalkyl ring or heterocycle and an aryl group or heteroaromatic ring, the ring structure may be linked by a fused ring or other means. L 10 It is empty or ringer. L 11 C may be empty or substituted. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group. W 10 is -OR 1 ;-COOR 1a ;-OCOOR 1a ;-COR 2 ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a ; or The file is JPEG2026086398000022.jpg1818, During the ceremony, R 1 and R 1a Each of these is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group. R 3 and R4 These are, independently, hydrogen and -COR 2b , -SO2R 5b , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 3 and R 4 These, together with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group. R 2 , R 2a , R 2b , R 5 , R 5a and R 5b These are, independently, hydrogen, -OH, and -NR. 3e R 4e , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d Or R 3e and R 4e These, along with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group.

[0121] In some embodiments, in formula II, Cy 10 and Cy 11 At least one of these is C which may be substituted. 6-10 The aromatic ring is an aromatic ring or a substituted 5-10 member heteroaromatic ring. In some embodiments, Cy 11 C may be substituted. 6-10 It is an aromatic ring or a substituted 5-10 membered heteroaromatic ring. 11 If L is a bicyclic or polycyclic aryl group or a heteroaromatic ring, 10 -Cy 10 and L 11 -W 10 Cy independently, via any ring 11 It may be connected to Cy 11 It may have a fused ring structure containing an aryl group or a heteroaromatic ring and a cycloalkyl group or a heterocyclic structure. In such embodiments, Cy 11 L is formed via one of the following: an aryl group or heteroaromatic ring and a cycloalkyl group or heterocyclic structure. 10 -Cy 10 and L 11 -W 10 It may be connected to, or instead, L 10 -Cy 10 and L 11 -W 10 One of them is Cy via an aryl group or heteroaromatic ring.11 It is connected to L 10 -Cy 10 and L 11 -W 10 The other is a cycloalkyl group or a heterocyclic structure via Cy 11 It is connected to.

[0122] In some embodiments, the compound of formula II has at least one benzene ring and Cy 10 -L 10 -Cy 11 It may have the following core structure as follows: JPEG2026086398000023.jpg66170 Here, Cy 10 This may be the left ring or the right ring in the figure above; that is, the figure is not restricted to a specific direction, where L 11 -W 10 It may be connected to either the left-hand ring or the right-hand ring, and both rings may be replaced.

[0123] In some embodiments, the compound of formula II is Cy 10 -L 10 -Cy 11 It may have the following core structure as follows: JPEG2026086398000024.jpg68170 Here, Cy 10 L may be the left ring or the right ring in the figure above, that is, the figure is not restricted to a particular direction, where L 11 -W 10 It may be connected to either the left-hand ring or the right-hand ring, and both rings may be replaced.

[0124] In some embodiments, Cy in formula II 10 and Cy 11 All of these are aryl groups or heteroaromatic rings. In some embodiments, the compound of formula II has formula II-1. JPEG2026086398000025.jpg2381, During the ceremony, Ar 10 and Ar 11Each of these can be substituted independently of C. 6-10 It is an aromatic ring or a substituted 5-10 member heteroaromatic ring. In some embodiments, Ar in formula II-1 10 and Ar 11 Each is independently a substituted benzene ring or a substituted 5 or 6-membered heteroaromatic ring. In some embodiments, Ar in formula II-1 10 and Ar 11 Each of these is independently a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring. In some embodiments, Ar in formula II-1 10 and Ar 11 One of them is a bicyclic aryl group or a bicyclic heteroaromatic ring, and each may be substituted, for example, in some embodiments, Ar 11 This may be a substituted bicyclic aryl group or a bicyclic heteroaromatic ring.

[0125] In some embodiments, Cy in formula II 11 is a benzene ring. In some embodiments, the compound of formula II has formula II-2. JPEG2026086398000026.jpg4160, During the ceremony, Ar 10 , L 10 , L 11 and W 10 This is defined in this application, see, for example, formula II-1, m is 0, 1, 2, or 3. R 20 Each time it appears, it independently emits halogen, -L 11’ -W 10’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 20 , or one R 20 and L 10 or L 11 These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. Here, -L 11’ -W 10’ Each time they appear, they are independently chosen, Here L 11’ Each time it appears, it may be replaced by an empty C independently. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group, and W 10’ Each time it appears, independently, -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or The file is JPEG2026086398000027.jpg1818, and here R 1 , R 1a , R 2 , R 2a , R 2b , R3 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 5a and R 5b This is defined in this application, see formula II, for example. Note that structural unit -L 11’ -W 10’ and -L 11 -W 10 Each instance of is chosen independently and may be identical or different.

[0126] In some embodiments, Cy in formula II 11 This is a benzo-condensed ring. In some embodiments, the compound of formula II has formula II-3. JPEG2026086398000028.jpg3460, During the ceremony, Ar 10 , L 10 , L 11 and W 10 This is defined in this application, see, for example, formula II-1, m is 0, 1, 2, or 3. R 20 Each time it appears, it independently emits halogen, -L 11’ -W 10’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 20 , or one R20 and L 10 or L 11 These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. Here L 11’ and W 10’ This is defined in this application, see, for example, formula II-2, and -L 11’ -W 10’ Each time it appears, it is independently chosen, and Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocycle, a benzene ring, or a 5 or 6 membered heteroaromatic ring, each of which may be substituted.

[0127] In some embodiments, Cy in formula II 11 is a benzo-condensed bicyclic aryl group or a heteroaromatic ring. For example, in some embodiments, Cy in formula II 11 It may have the following core structure. JPEG2026086398000029.jpg64147, During the ceremony, L 10 -Cy 10 and L 11 -W 10 Independently, Cy through one of the two rings 11 They may be linked together, and the benzene ring has 1-3 R as defined in this application. 20 It may be substituted with a group. For example, with respect to the benzothiophene ring, in some embodiments, L 10 -Cy 10 It may be connected to the thiophene ring, L 11 -W 10 L may be connected to a benzene ring, and vice versa, and in some cases, 10 -Cy 10 and L 11 -W 10 They may all be connected to the same ring, for example, a benzene ring.

[0128] In some embodiments, the compound of formula II may have any of the following structures. JPEG2026086398000030.jpg84170In formula, Cy 10 , L 10 , R 20 , m, R 21 , n, R 100a , L 11 and W 10 Cy is defined in this application, see, for example, formula II and subformula of this application, e.g., formula II-3. In some embodiments, Cy 10 This is defined for equation II-3, Ar 10 That is the case.

[0129] In some embodiments, the compound of formula II-3 may have formula II-4. JPEG2026086398000031.jpg3570, During the ceremony, Ar 10 , L 10 , R 20 , m, L 11 and W 10 This is defined in this application, see, for example, formula II-3, n is either 0 or 1. R 21 Each time it appears, it independently produces halogen, oxo, and -L. 11’ -W 10’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, where L 11’ and W 10’ This is defined in this application, see, for example, formula II-2, and -L 11’ -W 10’ Each time they appear, they are independently chosen, If valence permits, X 10 and X11 These are, independently, empty, -O-, -C(O)-, -S-, and -NR. 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, Here, R 100a This includes lone pairs of electrons (if applicable), hydrogen, and COR 2c , -SO2R 5c , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 100a R 20 or R 21 Forms a heterocycle or heteroaromatic ring which may be substituted with a group, R 101a and R 102a If present, these are independently hydrogen, -OH, and halogen; C may be substituted. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, substituted KarC 3-6 A cycloalkoxy group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group, or R 101a and R 102a These, together with the atoms to which they are bonded, form a substituted 3-7 membered cycloalkyl or heterocyclyl ring, or R 101a and R 102a One of them is R 20 or R 21 Together with the group, it forms a substituted cycloalkyl group or heterocyclyl ring, and R 2c and R 5cThese are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group. Or R 20 or R 21 and L 10 , X 10 or X 11 These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. X 10 or X 11 If it forms a double bond with one of the ring carbons, then this is R 101a and R 102a CR where all exist 101a R 102a This is not the case, because the valence of carbon exceeds 4. In such cases, R 101a and R 102a One of them does not exist, and X 10 or X 11 This is the CR as defined in this application. 101a or CR 102a X 10 or X 11 If it forms a double bond with one of the ring carbons, this is NR 100a It may also be the case that R 100a These are usually lone pairs of electrons.

[0130] In some embodiments, the compound of formula II has formula II-5. JPEG2026086398000032.jpg3767, During the ceremony, Ar 10 , L 10 , R 20 , m, R 21,n,L 11 and W 10 This is defined in this application, see, for example, formula II-4. Cy in formula II (for example, any of the aforementioned sub-formulas of this application, e.g., formulas II-1 to II-4) 10 and Cy 11 These may be linked directly or via multiple types of groups. For example, in some embodiments, L in formula II (e.g., formulas II-1 to II-5) 10 C may be empty, -C(O)-, or substituted. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, may be substituted C 3-6 Cycloalkylene group, substituted 4-7 membered heterocyclylene group, substituted phenylene group, substituted 5 or 6 membered heteroarylene group, -O-, -S-, -NR 100 -, -S(O)-, -SO2-, -X 1 -G 1 -, -X 2 -G 2 -X 2a -, -X 12 -G 10 -, -X 13 -G 11 -X 13a - or -CR 101 R 102 -and, Here, X 1 , X 2 and X 2a C may be substituted independently. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, may be substituted C 3-6 Cycloalkylene groups, substituted 4-7 membered heterocyclylene groups, substituted phenylene groups, substituted 5 or 6 membered heteroarylene groups, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, G 1 and G 2 C may be substituted independently. 1-4Alkylene group, substituted KilC 2-4 Alkenylene group, may be substituted C 3-6 Cycloalkylene group, substituted 4-7 membered heterocyclylene group, substituted phenylene group, substituted 5 or 6 membered heteroarylene group, -C(O)-, -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, Preferably, in some embodiments, -X 1 -G 1 - or -X 2 -G 2 -X 2a - does not include ON, SS, SN (excluding SO2-N bonds), or -C(O)-S bonds. X 12 , X 13 and X 13a C may be substituted independently. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, may be substituted C 3-6 Cycloalkylene groups, substituted 4-7 membered heterocyclylene groups, substituted phenylene groups, substituted 5 or 6 membered heteroarylene groups, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, and G 10 and G 11 -X 1 -G 1 - or -X 2 -G 2 -X 2a -and, In some embodiments, preferably, -X 12 -G 10 - or -X 13 -G 11 -X 13a - does not contain OO, ON, SS, SN (excluding SO2-N bonds), or -C(O)-S bonds or three (or more) consecutive heteroatoms, where O-SO2-O, O-SO2-N and N-SO2-N, R 100 and R 100a These are, independently, lone pairs of electrons (if applicable), hydrogen, and COR 2c , -SO2R 5c , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 This may be a cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- to 7-membered heterocyclic group. R 101 , R 101a , R 102 and R 102a These are, independently, hydrogen, -OH, halogen; and C which may be substituted. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, substituted KarC 3-6 A cycloalkoxy group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group, or R 101 and R 102 , or R 101a and R 102a These, together with the atoms to which they are bonded, form a substituted 3-7 membered cycloalkyl or heterocyclyl ring.

[0131] In some embodiments, L in formula II 10 It may be empty, and Cy 10 is Cy 11 It is directly connected. In some embodiments, L in formula II 10 These are empty, -O-, -C(O)-, -S-, and -NR. 100 -, -S(O)-, -SO2-, or -CR 101 R 102-may be. In some embodiments, L in formula II 10 is -X 1 -G 1 - or -X 2 -G 2 -X 2a - may be, and here, X 1 , X 2 and X 2a These are independently -O-, -C(O)-, -S-, and -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a - and G 1 and G 2 These are independently -C(O)- and -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a - is

[0132] In some embodiments, L in formula II 10 is -X 12 -G 10 -May also be the case. In some embodiments, X 12 C may be substituted. 2-4 Alkenylene group, preferably an alkenylene group. The filename is JPEG2026086398000033.jpg1241, and G 10 is -X 1 -G 1 - or -X 2 -G 2 -X 2a -and here, X 1 , X 2 and X 2a These are independently -O-, -C(O)-, -S-, and -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a - and G 1 and G 2 These are independently -C(O)- and -NR 100a -, -S(O)-, -SO2-, or -CR 101a R 102a - is In some preferred embodiments, L in formula II 10 teeth JPEG2026086398000034.jpg1241 JPEG2026086398000035.jpg2251 or The filename JPEG2026086398000036.jpg1829 is also acceptable.

[0133] In some embodiments, the compound of formula II may have the following core structure. JPEG2026086398000037.jpg158126In formula, L 11 -W 10 It may be directly connected to any one of the rings, preferably to one of two benzene rings or to a single benzene ring, where each ring can be replaced by one or more suitable substituents described herein, for example, each substituent being F;Cl;-OH;-NH2;-SO2NH2;-SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl);-COOH; JPEG2026086398000038.jpg1818;-C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl); C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 Alkyl alkyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkenyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkynyl group; C 1-4A C optionally substituted with 1 - 3 substituents independently selected from an alkyl group and fluorine 3-6 cycloalkyl group; C 1-4 A C optionally substituted with 1 - 3 substituents independently selected from an alkyl group and fluorine 3-6 cycloalkoxy group; or C 1-4 An alkyl group, C 1-4 An alkoxy group, -OH, -NH₂, and a C optionally substituted with 1 - 3 substituents independently selected from fluorine 1-4 alkoxy group; An optionally substituted C 3-6 cycloalkyl group; An optionally substituted 4 - 10 - membered heterocyclic group; An optionally substituted 5 - 10 - membered heteroaryl group; or an optionally substituted C 6-10 aryl group may be independently selected. For example, in some embodiments, L 11 -W 10 is NH₂ or NH(C 1-4 alkanoyl), is linked to one of the two benzene rings, or to the sole benzene ring, and the other ring may be substituted with 1 or 2 substituents selected from a methyl group and a methoxy group. In some specific embodiments, the compound of formula II has a formula according to formula II - 6 or II - 7. JPEG2026086398000039.jpg36151, wherein, L 11 , W 10 , R 20 and m are defined in the present application. For example, refer to formula II - 3, p is 0, 1, 2, 3 or 4, R 22 is, each time it appears, independently, halogen, -L 11’ -W 10’ , an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 3-6A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 22 These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring, where L 11’ and W 10’ This is defined in this application, see, for example, formula II-2, and -L 11’ -W 10’ Each time they appear, they are chosen independently. L in equation II (for example, any sub-equation, e.g., equations II-1 to II-7) 11 It is usually empty and immediately applicable, W 10 The base is Cy 11 It is directly connected. In some embodiments, L in formula II 11 is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It may also be a heteroalkylene group. For example, W 10 The group is via a methylene group or an ethenyl group. 11 It may also be connected to it. Multiple types of W 10 The group can be applied to compounds of formula II (e.g., formulas II-1 to II-7). In a preferred embodiment, W 10 Each time the group appears, it independently becomes -OH, -NH2, -SO2NH2, -SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl), -COOH, JPEG2026086398000040.jpg1818, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 Alkyl) and here each C 1-4 Alkyl groups are independently C 1-4 Alkyl alkyl group, C1-4 It may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, W in formula II 10 The groups are -OH, -OMe, -NH2, -SO2NH2, -SO2NH(acetyl), -COOH, The filename is JPEG2026086398000041.jpg1818 or -OC(O)-CH3. As described in this application, L 11’ -W 10’ In some embodiments, Cy 10 or Cy 11 For example, Ar 10 Or Ar 11 The substituent may be selected for use in the following case: 11’ Each time it appears, for example, Ar 10 Or Ar 11 Regarding (if applicable), it may be empty independently, i.e., W 10’ The base is Cy 10 or Cy 11 It may be directly connected to C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It is a heteroalkylene group. For example, W 10’ The base is, for example, Ar 10 Or Ar 11 Regarding (if applicable), Cy via a methylene group or ethenyl group 10 or Cy 11 It may be connected to. If applicable, W in formula II (including any of the aforementioned subformulas of this application, e.g., formulas II-1 to II-7) 10’ Each time it appears, it independently produces -OH and -NH. 2 -SO2NH2, -SO2NH(C 1-4 Alkyl), -SO2NH(C 1-4 Alkanoyl), -COOH, JPEG2026086398000042.jpg1818, -C(O)(OC 1-10(alkyl), -C(O)(O-C 2-10 (alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 (alkyl)-, -O-(CO)-(C 1-4 (alkyl), -O-(C 1-4 (alkyl) may also be, where each C 1-4 alkyl group is independently selected from C 1-4 alkyl group, C 1-4 alkoxy group, -OH, -NH2, and 1-3 substituents independently selected from fluorine may be substituted. In some embodiments, when applicable, W in formula II 10’ each instance of may be -OH, -OMe, -NH2, -SO2NH2, -SO2NH(acetyl), -COOH or -O-C(O)-CH3. Multiple types of groups may be applicable to R 20 , R 21 and R 22 in any applicable formula II (for example, when applicable, formula II-1 to II-7). In some embodiments, each of R 20 , R 21 and R 22 each time it appears is independently F; Cl; -OH; -NH2; -SO2NH2; -SO2NH(C 1-4 (alkyl); -SO2NH(C 1-4 (alkanoyl); -COOH; JPEG2026086398000043.jpg1818; -C(O)(O-C 1-10 (alkyl), -C(O)(O-C 2-10 (alkenyl), -OC(O)NH2; -OC(O)NH(C 1-4 (alkyl)-; -O-(CO)-(C 1-4 (alkyl); C 1-4 alkyl group, C 1-4 alkoxy group, -OH, -NH2, and may be substituted with 1-3 substituents independently selected from fluorine C 1-4 alkyl group; C 1-4 alkyl group, C 1-4 alkoxy group, -OH, -NH2, and may be substituted with 1-3 substituents independently selected from fluorine C 2-6Alkenyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkynyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkoxy group; or C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 It may be an alkoxy group. In some embodiments, R 20 , R 21 and R 22 Each of these, whenever it appears, independently consists of F;Cl;-OH;-NH2, -SO2NH2, and -SO2NH(C 1-4 Alkyl), -SO2NH(C 1-4 Alkanoyl), -COOH; JPEG2026086398000044.jpg1818;-C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl);-O-(C 1-6 Alkyl);-O-(C 2-6 Alkenil); C 1-4 Alkyl alkyl group, C 1-6 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-6 Alkyl alkyl group; or C 1-4 Alkyl alkyl group, C 1-6 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 It may be an alkenyl group. 20 , R21 and R 22 Each of these, whenever it appears, independently produces -OH, C 1-4 Alkyl alkyl group, C 2-6 Alkenyl group or -O-(C 1-4 It may be alkyl. In some embodiments, R 20 , R 21 and R 22 Each of these, whenever it appears, independently of -OH, -OMe, or It may also be JPEG2026086398000045.jpg1622. In some embodiments, R 20 One or more instances of R 21 One or more instances of and / or R 22 One or more instances of are independently selected, such as L described in this application. 11’ -W 10’ That's fine. Typically, m and p are 0, 1, 2, or 3, preferably 1 or 2, when applicable. Typically, n is 0, 1, or 2, preferably 0 or 1, when applicable.

[0134] In some embodiments, the compound of formula II may have a formula represented by any one of formulas II-8 to II-10. JPEG2026086398000046.jpg3569, JPEG2026086398000047.jpg3766 or JPEG2026086398000048.jpg3368, During the ceremony, R 20 , R 22 m and p are defined herein. In some embodiments, m is 1 or 2, and p is 1, 2, or 3. In some embodiments, R 20 and R 22 Each of these, whenever it appears, independently consists of F;Cl;-OH;-NH2, -SO2NH2, and -SO2NH(C 1-4 Alkyl), -SO2NH(C 1-4 Alkanoyl), -COOH; JPEG2026086398000049.jpg1818;-C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl);-O-(C 1-6 Alkyl);-O-(C 2-6 Alkenil); C 1-4 Alkyl alkyl group, C 1-6 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-6 Alkyl alkyl group; or C 1-4 Alkyl alkyl group, C 1-6 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 It is an alkenyl group.

[0135] In some embodiments, any applicable structural unit in Formula II JPEG2026086398000050.jpg2132 may be selected from the following: JPEG2026086398000051.jpg87104 In some specific embodiments, the compound of formula II is JPEG2026086398000052.jpg3167, JPEG2026086398000053.jpg4267, JPEG2026086398000054.jpg3561 or JPEG2026086398000055.jpg3561, Alternatively, it may be a pharmaceutically acceptable salt or ester.

[0136] In some embodiments, the compounds of the present application may be characterized by having formula III or by being pharmaceutically acceptable salts or esters. JPEG2026086398000056.jpg1942, During the ceremony, Ar 20is an aromatic ring that may be substituted (e.g., C 6-10 Aromatic ring) or a substituted heteroaromatic ring (e.g., a 5-10 member heteroaromatic ring), L 20 C may be empty or substituted. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group. W 20 is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a ; or The file is JPEG2026086398000057.jpg1818, Here, R 1 and R 1a Each of these is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group. R 3 and R 4 These are, independently, hydrogen and -COR 2b , -SO2R 5b , substitution may be C1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 3 and R 4 These, together with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group. R 2 , R 2a , R 2b , R 5 , R 5a and R 5b These are, independently, hydrogen, -OH, and -NR. 3e R 4e , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d Or R 3e and R 4e These, along with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group.

[0137] In some embodiments, Ar in formula III 20 is a substituted benzene ring or a substituted 5 or 6-membered heteroaromatic ring. For example, in some embodiments, Ar in formula III 20 The Ar in formula III may be a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring. In some embodiments, the Ar in formula III 20 L may be a substituted bicyclic aryl group or a bicyclic heteroaromatic ring, each of which may be substituted. In such embodiments, L 20 -W 20 It may be connected to either one of the two rings.

[0138] In some embodiments, Ar in formula III 20 The ring may be a substituted benzene ring, where two adjacent substituents, together with the carbon to which they are connected, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. For example, in some embodiments, Ar in Equation III 20 The Ar in formula III may be a benzo-condensed bicyclic aryl group or a heteroaromatic ring. For example, in some embodiments, the Ar 20 It may have the following structure. JPEG2026086398000058.jpg64147, During the ceremony, -L 20 -W 20 It may be connected to either of the two rings, where one or both rings may be substituted.

[0139] In some embodiments, the compound of formula III may have formula III-1, III-2, or III-3. JPEG2026086398000059.jpg68112In formula, L 20 and W 20 This is defined in this application, m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3. R 30 and R 31 Each of these, each time it appears, independently of halogen, -L 20’ -W 20’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, where -L 20’ -W 20’ Each time it appears, it is independently chosen, and here L 20’ Each time it appears, it may be replaced by an empty C independently. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group, and W 20’ Each time it appears, independently, -OR1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or The file is JPEG2026086398000060.jpg1818, and here, its R 1 , R 1a , R 2 , R 2a , R 2b , R 3 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 5a and R 5b This is defined in this application, see, for example, formula III, Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocycle, a benzene ring, or a 5 or 6 membered heteroaromatic ring, each of which is independently selected from 1 to 3 R groups. 31 It may be replaced by, If valence permits, X 20 and X 21 These are, independently, empty, -O-, -C(O)-, -S-, and -NR. 100a -, -S(O)-, -SO2-, or -CR 101a R 102a -and, Here, R 100a This includes lone pairs of electrons (if applicable), hydrogen, and COR2c , -SO2R 5c , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 100a and R 30 or R 31 One of them, together with the atom to which they are bonded, forms a substituted heterocycle or heteroaromatic ring, for example, a substituted 5 or 6-membered heteroaryl group or a substituted 4-7-membered heterocyclic group. R 101a and R 102a If present, these are independently hydrogen, -OH, and halogen; C may be substituted. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, substituted KarC 3-6 A cycloalkoxy group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group, or R 101a and R 102a These, together with the atoms to which they are bonded, form a substituted 3-7 membered cycloalkyl or heterocyclyl ring, or R 101a and R 102a One of them is R 30 or R 31 Together with the group, it forms a substituted cycloalkyl group or heterocyclyl ring, R 2c and R 5c These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group. Alternatively, two adjacent R 30 or two adjacent R 31 , or R 30 or R 31 and X 20 or X 21 These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. X 20 or X 21 If it forms a double bond with one of the ring carbons, this is R 101a and R 102a CR where all exist 101a R 102a This is not the case, because the valence of carbon exceeds 4. In such cases, R 101a and R 102a One of them does not exist, and X 20 or X 21 This is the CR as defined in this application. 101a or CR 102a X 20 or X 21 If it forms a double bond with one of the ring carbons, this is NR 100a It may also be the case that R 100a These are usually lone pairs of electrons. Note: Structural unit -L 20’ -W 20’ and -L 20 -W 20 Each instance of is chosen independently and may be identical or different.

[0140] In some embodiments, the compound of formula III may have any of the following structures. JPEG2026086398000061.jpg197170In formula, R30 , m, R 31 , n, R 100a , L 20 and W 20 This is defined in the present application, for example, with reference to formula III and subformulas of the present application, for example, formulas III-1 to III-3, where, for the tricyclic structure, the piperidine ring or morpholine ring may be substituted. L in Equation III (for example, any sub-equation, e.g., Equations III-1 to III-3) 20 It is usually empty, that is, W 20 The base is Ar 20 It is directly connected. In some embodiments, L in Equation III 20 is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It may also be a heteroalkylene group. For example, W 20 The group is via a methylene group or an ethenyl group, and is Ar 20 It may also be connected to it. Multiple types of W 20 The group can be applied to compounds of formula III (for example, any sub-formula, e.g., formulas III-1 to III-3). In a preferred embodiment, W in formula III 20 -OH, -COOH, JPEG2026086398000062.jpg1818, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -NH2, -SO2NH2, -SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl), -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 It may also be alkyl, where each C 1-4 Alkyl groups are independently C 1-4 Alkyl alkyl group, C 1-4It may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, W in formula III (e.g., any sub-formula, e.g., formulas III-1 to III-3) 20 The groups are -OH, -NH2, -SO2NH2, -SO2NH (acetyl), JPEG2026086398000063.jpg1818, -C(O)-(O-C8 alkyl), -COOH or -OC(O)-CH3. As described in this application, L 20’ -W 20’ In some embodiments, Ar 20 The substituent may be selected for use in the following case: L in formula III (including any of the aforementioned subformulas of this application, e.g., formulas III-1 to III-3). 20’ Each time it appears, it may be empty independently, that is, when applied, W 20’ The base is Ar 20 , or C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 It may be directly attached to the heteroalkylene group. For example, when applied, W 20’ The group is an Ar group via a methylene group or an ethenyl group. 20 It may be connected to. If applicable, W in formula III (including any of the aforementioned subformulas of this application, e.g., formulas III-1 to III-3) 20’ Each time it appears, independently, -OH, -COOH, JPEG2026086398000064.jpg1818, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -NH2, -SO2NH2, -SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl), -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 It may also be alkyl, where each C 1-4 Alkyl groups are independently C1-4 Alkyl alkyl group, C 1-4 It may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, when applied, W in formula III 20’ Each instance of is -OH, -NH2, -SO2NH2, -SO2NH(acetyl), JPEG2026086398000065.jpg1818, -COOH, -C(O)(O-C8 alkyl), or -OC(O)-CH3 may also be used. Multiple types of bases are R in any applicable equation III (e.g., any sub-equations, e.g., equations III-1 to III-3). 30 and R 31 Applicable to some embodiments, R 30 and R 31 Each of these, whenever it appears, independently consists of F;Cl;-OH;-COOH;-OC(O)NH2;-OC(O)NH(C 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl); C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 Alkyl alkyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkenyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkynyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkoxy group; or C 1-4 Alkyl alkyl group, C 1-4C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 It may be an alkoxy group. In some embodiments, R 30 and R 31 Each of these, whenever it appears, independently becomes -OH, C 2-6 Alkenyl group, -O-(C 1-4 Alkyl), -COOH or -C(O)(OC 1-10 It may be alkyl. In some embodiments, R 30 and R 31 Each of these may be -OH or -OMe whenever it appears. In some embodiments, R 30 One or more instances of and / or R 31 One or more instances of are independently selected, such as L described in this application. 20’ -W 20’ That's fine. Typically, m is 0, 1, 2, or 3, preferably 2 or 3. Typically, n is 1, 2, or 3.

[0141] In some embodiments, the present disclosure relates to compounds Further details are provided, including JPEG2026086398000066.jpg3178, or pharmaceutically acceptable salts or esters.

[0142] In some embodiments, the present disclosure relates to compounds JPEG2026086398000067.jpg3164, or a further pharmaceutically acceptable salt or ester is provided, where q is 1, 2, 3, 4, or 5, and Glu is a glucose residue. In some particular embodiments, the disclosure further provides JPEG2026086398000068.jpg6573 further provides pharmaceutically acceptable salts or esters.

[0143] In some embodiments, the compounds of the present application may be alkaloids having antibacterial activity. As shown in the present application, some indole alkaloids, such as vinca alkaloids, tabasonin, vindrin, vinblastine, and vincristine, have been shown to be able to effectively kill microorganisms such as Bacillus megatherium. In some embodiments, the compounds of the present application are characterized by formula IV-1 or IV-2, and are tabasonin or vindrin and its derivatives. JPEG2026086398000069.jpg51123, During the ceremony, R 40 is hydrogen;-COR 2 ;-COOR 1a ;-SO2R 5a ; a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted heterocyclic group, R 41 is -OR 1 ;-OCOOR 1a ;-OCONR 3b R 4b ;-OCOR 2a ; or -OSO2R 5a And n is either 0 or 1, R 42 , R 43 and R 44 These are, independently, hydrogen, -OR 1 OCOR 2a ; or -OSO2R 5a And, L 30 is empty or a methylene group, W 30 is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-OSO2NR3d R 4d ;-OCOR 2a ; or -OSO2R 5a And, Here, R 1 and R 1a Each of these is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group, and R 3 and R 4 These are, independently, hydrogen and -COR 2b , -SO2R 5b , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 3 and R 4 These, together with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group. R 2 , R 2a , R 2b , R 5 , R 5a and R 5b These are, independently, hydrogen, -OH, and -NR. 3e R 4e , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, and R 3a , R3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d Or R 3e and R 4e These, along with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group.

[0144] In some embodiments, the compound of formula IV-1 or IV-2 may have a formula represented by one of formulas IV-3 to IV-6. JPEG2026086398000070.jpg81163JPEG2026086398000071.jpg77109 or JPEG2026086398000072.jpg7483In formula, R 45 It is either a hydrogen atom or a methyl group.

[0145] In some embodiments, one of the R values ​​from formulas IV-1 to IV-6 is used. 40 is hydrogen, C 1-4 Alkyl alkyl group or C 1-4 It may also be an alkanoyl group. L in equations IV-1 to IV-630 It is usually empty. However, in some embodiments, L in formulas IV-1 to IV-6 30 CH2 may also be used. W in equations IV-1 to IV-6 30 These are typically carboxylic acid derivatives, amine derivatives, or alcohol derivatives that can be used in the compositions and methods of this application. The naturally occurring indole alkaloid tabasonine has a CO2Me group. 30 Included as L 30 The CO2Me group is empty. The CO2Me group can be converted to the corresponding acid, amide, etc., via normal conversion, or reduced or converted to an amine via a rearrangement, such as the Curtius rearrangement. In some embodiments, W in formulas IV-1 to IV-6 30 -OH, -NH2, -OSO2NH2, -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 Alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-,-O-(CO)-(C 1-4 Alkyl), -O-(C 1-4 It may also be alkyl, where each C 1-4 Alkyl groups are independently C 1-4 Alkyl alkyl group, C 1-4 It may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. In some embodiments, W in formulas IV-1 to IV-6 30 -OH, -NH2, -OSO2NH2, -C(O)-(O-C8alkyl), -COOH, or -OC(O)NH2 may also be used. In some specific embodiments, the compound may have the following structure. JPEG2026086398000073.jpg3895.

[0146] In some embodiments, the compounds of the present application may be glycosides having antimicrobial activity, or pharmaceutically acceptable salts or esters. As shown in the present application, some glycosides, such as ginsenosides and gallic acid glycosides, have been shown to be able to effectively kill microorganisms such as Bacillus megatherium. Other useful glycosides include any one of these glycosides known to have antimicrobial activity in the art, for example, glycosides characterized in that their corresponding aglycone is a phenol compound, a flavonoid, a coumarin, benzoic acid, or a sterol. Usually, the glycoside is a glucoside, but other glycosides may be used. In some embodiments, the glycoside may be characterized as amphiphilic, thereby disrupting biofilms and conferring the antimicrobial activity of the glycoside. In some embodiments, the glycoside may be characterized as a saponin, for example, and may include multiple plant-derived glycosides that can function as a "surfactant" and contribute to the killing of bacteria.

[0147] In some embodiments, the glycoside of the present invention may be characterized by formula V. JPEG2026086398000074.jpg4472In formula, Each R 50 Independently, hydrogen, -L 50 -D is an oxygen protecting group or sugar residue. L 50 is empty or -C(O)-, D is an aryl group that may be substituted (for example, C 6-10 An aryl group), a substituted heteroaryl group (e.g., a 5-14 member heteroaryl group), a substituted condensed ring (e.g., an 8-14 member, e.g., a benzo-condensed cycloalkyl / heterocyclic group, a pyrido-condensed cycloalkyl / heterocyclic group) comprising two or more rings independently selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group, or a steroid residue having the formula VA, JPEG2026086398000075.jpg4267 Here, if the valence allows, JPEG2026086398000076.jpg826 is a steroid skeleton or any R 51 It may also be connected to formula VA via a base, Here R 51 Each instance is independently a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted -OH group, an oxo group, a halogen group, a substituted cycloalkyl group, a substituted alkoxy group, a substituted cycloalkoxy group, a substituted amino group, a substituted phenyl group, a substituted heteroaryl group, or a substituted heterocyclic group, or two R groups. 51 The groups, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. m is an integer between 1 and 8, and Here, -L 50 -D is chosen independently each time it appears.

[0148] Several embodiments, each R 50 It is hydrogen.

[0149] In some embodiments, 1 to 4 R 50 It is selected independently - L 50 -D is also acceptable. Two or more -L 50 -When the D units are linked to the pyranose units in formula V, they are preferably the same. In some embodiments, one or more (e.g., one or two) R 50 The sugar residue may be a sugar residue linked to the rest of formula V via a glycosidic bond. In some embodiments, the sugar residue is a glucose residue or a rhamnose residue. L in equation V 50 The group may be empty or a carbonyl group, i.e., -C(O)-, depending on whether the linking group is a phenolic -OH or COOH group derived from benzoic acid or a heteroaryl counterpart. Multiple types of residues can be used as D, and are typically residues derived from phenolic compounds, coumarins, flavonoids, or sterols. In some embodiments, they may have antibacterial activity without glycosidic units.

[0150] In some embodiments, D may be selected from the following substituted rings. JPEG2026086398000077.jpg80123In formula, R 100a This includes lone pairs of electrons (if applicable), hydrogen, nitrogen protecting groups, and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group, or R 100a It forms a heterocyclic or heteroaromatic ring which may be substituted with a phenyl group or a pyridine ring. Here, JPEG2026086398000078.jpg826 may be concatenated to D via any available location, and, Each ring system of D may be substituted with 1-5 (e.g., 1, 2, or 3) substituents, each substituent independently of -OH;-COOH;-C(O)(OC 1-10 Alkyl);-C(O)(OC 2-10 Alkenyl;-OC(O)NH2;-OC(O)NH(C) 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl);-NH2;-SO2NH2;-SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl; halogen; substitution May C 1-6 Alkyl alkyl group; substitution may be C 2-6 Alkenyl group; substitution is stored in C 2-6 Alkynyl group; substituted KadC 3-6 Cycloalkyl groups; may be substituted with C 1-6Alkoxy group; substitution may be C 3-6 Selected from a cycloalkoxy group; an optionally substituted amino group; an optionally substituted phenyl group; an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4- to 7-membered heterocyclic group.

[0151] In some embodiments, each of the ring systems of D as described above may be substituted with 1 to 5 substituents, each substituent independently of F;Cl;-OH;-COOH;-C(O)(OC 1-10 Alkyl);-C(O)(OC 2-10 Alkenyl;-OC(O)NH2;-OC(O)NH(C) 1-4 Alkyl)-;-O-(CO)-(C 1-4 Alkyl);-NH2;-SO2NH2;-SO2NH(C 1-4 Alkyl);-SO2NH(C 1-4 Alkanoyl); C 1-4 The C group may be substituted with 1-3 substituents independently selected from the alkyl group. 1-4 Alkyl alkyl group; C 1-4 Alkoxy groups, -OH, -NH2, and fluorine; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkenyl group; C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 2-6 Alkynyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkyl group; C 1-4 C may be substituted with 1-3 substituents independently selected from alkyl groups and fluorine. 3-6 Cycloalkoxy group; or C 1-4 Alkyl alkyl group, C 1-4 C may be substituted with 1 to 3 substituents independently selected from alkoxy groups, -OH, -NH2, and fluorine. 1-4 Selected from alkoxy groups.

[0152] In some embodiments, D may be selected from the following: JPEG2026086398000079.jpg210125, During the ceremony, Each phenolic OH group may be linked to a sugar (e.g., glucose) via a glycosidic bond.

[0153] In some embodiments, D is derived from sterols. For example, in some embodiments, D is The filename is JPEG2026086398000080.jpg4257. During the ceremony, R 52 is a substituted alkyl group or a substituted alkenyl group, Here, each of the remaining -OH groups in D may be linked to a sugar via a glycosidic bond. Preferably, R 52 teeth The filename could also be JPEG2026086398000081.jpg1235. In any of the embodiments described above, the glycoside may have formula V-1 or V-2. JPEG2026086398000082.jpg82104 or JPEG2026086398000083.jpg80127 In some embodiments, the glycoside may be a compound selected from the following: JPEG2026086398000084.jpg5360 and JPEG2026086398000085.jpg6655.

[0154] In some embodiments, the compound of the present application may be one or more compounds selected from benzoic acid, benzyl alcohol, coumarins, catechols, polyphenols, chalconoids (including licochalcones), stilbenes such as resveratrol and isoresveratrol, phenolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acid, caffeic acid, ferulic acid, chlorogenic acid, sinapic acid, flavonoids such as catechin, naringenin, quercetin, rutin, and chrysin, tannins such as ellagic acid, and pharmaceutically acceptable salts or esters and their glycosides.

[0155] In some embodiments, the compound of the present application may be one or more of compounds 1 to 8 or pharmaceutically acceptable salts or esters. JPEG2026086398000086.jpg40361, JPEG2026086398000087.jpg43392, JPEG2026086398000088.jpg33363, JPEG2026086398000089.jpg30544, JPEG2026086398000090.jpg28505, JPEG2026086398000091.jpg27616, JPEG2026086398000092.jpg55637, and JPEG2026086398000093.jpg62528

[0156] The compounds of this application may or may not be obtained by isolation from natural sources, or may be prepared by conventional chemical synthesis. For example, each of compounds 1 to 8 is commercially available and identified as a component in plants. Unless otherwise indicated, in any of the foregoing embodiments of this application, the compounds may be derived from synthetic sources. Unless otherwise indicated, in any of the foregoing embodiments of this application, the compounds may exist in a separated form or in a substantially pure form. The term “separated form” refers to a compound that has been separated and / or concentrated from its source (e.g., a synthetic reaction mixture or a natural source). Such separated compounds are usually substantially pure, for example, with a purity of 80%, 85%, 90%, 95% or higher by weight. It should also be understood that a composition containing a compound in a separated or substantially pure form, such as a pharmaceutical composition, means that the compound has been separated or purified, i.e., is in a separated or substantially pure form, before being mixed with other components of the composition.

[0157] The synthetic chemical transformations and protecting group methods (protection and deprotection) available for the synthesis of the compounds to be applied are known in this art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd version, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions of the literature.

[0158] Pharmaceutical composition In some embodiments, the present invention relates to a pharmaceutical composition comprising one or more compounds of the present disclosure and any pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, capsule materials or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents and mixtures thereof. Furthermore, several types of excipients for preparing pharmaceutical compositions and known techniques for preparing them are disclosed, as described in Remington's The Science and Practice of Pharmacy, 21st edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference).

[0159] A pharmaceutical composition may contain one or more compounds from the present disclosure. For example, in some embodiments, a pharmaceutical composition may contain a compound of formula I, II, III, IV-1, IV-2, V, any variant thereof, or any of compounds 1 to 8, or a pharmaceutically acceptable salt or ester. Unless otherwise indicated, in any of the above embodiments of the Application, a pharmaceutical composition may contain a compound selected from compounds 1 to 8 or a pharmaceutically acceptable salt or ester. Unless otherwise indicated, in any of the above embodiments of the Application, a pharmaceutical composition may not contain, or substantially not contain, a compound selected from compounds 1 to 8 or a pharmaceutically acceptable salt or ester.

[0160] Pharmaceutical compositions may contain varying amounts of the compounds of this disclosure, depending on several factors, such as the expected use and efficacy of the compounds. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of the compounds of this disclosure and pharmaceutically acceptable excipients. In some embodiments, the therapeutically effective amount of the compounds of this disclosure may be an amount that effectively treats AMD (e.g., wet AMD, dry AMD) as described in this application, and this depends on the person being treated, the stage and severity of the AMD, the composition of the compounds contained, the time of administration, the route of administration, the duration of treatment, the potency of the compounds, their clearance, and whether or not other pharmaceuticals are administered simultaneously. In some embodiments, the therapeutically effective amount of the compounds of this disclosure may be an amount that effectively kills or inhibits the growth of microorganisms, such as Bacillus megatherium, in, for example, the eyes (e.g., intraocular space), blood, and / or the gastrointestinal tract, such as the intestines. In some embodiments, the therapeutically effective dose of the compound of the Disclosure may be an amount that effectively kills or inhibits the growth of microorganisms in, for example, the eyes (e.g., intraocular space), blood, and / or the gastrointestinal tract, such as the intestines, one or more of which are selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae. In some embodiments, the therapeutically effective dose of the compound of the Disclosure may be an amount that effectively treats soft drusen symptoms, for example, by reducing soft dorsenoid lesions.

[0161] In several embodiments, the pharmaceutical compositions of the present application may be used to treat AMD and / or to kill or inhibit the growth of the microorganism of the present application, such as Bacillus megatherium. The microorganism of the present application is not particularly limited and usually relates to bacteria found in the intraocular space of a subject's eye, more preferably to microorganisms associated with AMD, such as microorganisms that are concentrated in AMD patients. Unless otherwise specified, in any of the embodiments of the present application, the microorganism may include Bacillus megatherium. In some embodiments, the microorganisms may include one or more selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae.

[0162] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other ingredients in the pharmaceutical composition of the present application are determined by the identity, body type, and / or circumstances of the patient receiving treatment, and further vary depending on the route of administration of the composition.

[0163] The pharmaceutical compositions of this application may be prepared to be delivered via any known delivery route, which includes, but is not limited to, oral, injectable or infusion, topical, intraocular, or inhaled.

[0164] In some embodiments, the pharmaceutical composition may be prepared for oral administration. The oral formulation may exist as individual units containing a predetermined amount of the active compound, such as capsules, pills, cachets, lozenges, or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil in water or water in oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Suitable non-limiting excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. It contains oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactant, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0165] In some embodiments, the pharmaceutical composition is prepared for injection or infusion, e.g., intravenous injection or infusion, subcutaneous or intramuscular injection, or intraocular injection, e.g., intravitreal injection. The injectable / infusionable formulation may be, for example, an aqueous solution, suspension, depot, implant or emulsion. Excipients for preparing injectable / infusionable formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof. In some embodiments, the pharmaceutical composition is prepared for intraocular administration, e.g., intravitreal injection.

[0166] In some embodiments, the pharmaceutical composition is prepared for topical use. Topical formulations and excipients for topical formulations are known in the art.

[0167] The compounds of this disclosure may be used as single therapies, in combination with each other, or in combination therapies. For example, in some embodiments, the pharmaceutical compositions of the Application may further comprise another antibiotic and / or anti-VEGF agent. In some embodiments, such antibiotics and / or anti-VEGF agents may be contained in a single dosage form. In some embodiments, any commercially available (e.g., FDA-approved) antibiotic and anti-VEGF agent may be used in combination with the compounds and compositions of the Application. In some embodiments, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or an azole antibiotic or a combination thereof. For example, in some embodiments, the antibiotic is a β-lactam antibiotic, such as penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pivampicillin, pibmecillinum, ticarcillin, cephalosporins such as cephastril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapirin, cephatolidin, cefazflur, cefazedone, cephalosporins Fazolin, cefalazine, cefuroxazine, ceftezol, cefaclor, cefmandol, cefmetazole, cefonisid, cefotetan, cefoxitin, cefprodil, cefuroxime, cefzonam, cefcapene, cefdaroxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefozidime, cefotaxime, cefpimisole, cefpodoxime, cefteram, ceftibuten, ceftiofur, cephthaloline, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclizine, cefepime, ceffluprenum, cefoselis, cefozopran,Cefpirome, cefquinome, ceftobiprole, cephthaloline, cefaclomedin, cephaloram, cephaparol, cefcanel, cephedorol, cefenpidone, cefetrizole, cefibitril, cefmatilen, cefmepidium, cefobecin, cefoxazole, cefurotil, cefsumide, cefuratime, ceftioxide, thienamicin derivatives, monobactam derivatives, β-lactamase inhibitors, methoxypenicillins; aminoglycoside antibiotics, such as streptomycin and gentamicin. Syn, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribomycin, micronomisomycin, azithromycin, dibekacin, shisomycin, netylmycin, paromomycin, bramycin, etc.; tetracycline antibiotics, e.g., tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; chloramphenicol antibiotics, e.g., chloramphenicol, thianphenicol, etc.; macrolide antibiotics Antibiotics, such as erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, medimycin, josamycin, azithromycin, clarithromycin, dylithromycin, roxithromycin, telithromycin, etc.; Glycopeptide antibiotics, such as vancomycin, norvancomycin, teicoplanin, etc.; Quinolone antibiotics, such as norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, mo Xyfloxacin, becifloxacin; nitroimidazole antibiotics, e.g., metronidazole, tinidazole, ornidazole; rifamycin antibiotics, e.g., rifampicin; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine.The polymyxin B combination may include one or more of the following: polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / gramicidin, etc.

[0168] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, salvarsan, azithromycin, azurocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cephalothin, cephamandol, cefazolin, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprodil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, ceffuroxime, chloramphenicol, Cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dalfopristin, dapsone, daptomycin, dicloxacillin, zilithromycin, doripenem, doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, loracalbef, mafenide, meropenem, methoxypenicillin, metronidazole Zole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netylmycin, nitrofurantoin, oxacillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifamycin, rifapentin, rifaximin, roxithromycin, silver sulfadiazine, spectinomycin, streptomycin, sulba Tam, sulfacetamide, sulfadiazine, sulfamethizol, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavancin, telithromycin, temocillin, tetracycline, thianphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, trimethoprim, troreoandmycin, vancomycin, enoxacin, lomefloxacin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin,Moxifloxacin, ofloxacin, norfloxacin, cefotetan, cefonisid, cephaladine, cefapillin, cephalothin, cefmetazole, cefotaxime, moxalactam, cefepime, cephthaloline fosamil, ceftoviprole, dalbavancin, demeclocycline, metacycline, ertapenem, fidaxomicin, geldanamycin, harbimycin, posizolid, radezolid, Antibiotics may be selected from Torezolid, Oritavancin, Spiramycin, Sulfadimethoxine, Sulfonamidochrysoidine, Gemifloxacin, Nadifloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Teixobactin, Malacidins, and combinations thereof. Antibiotics may be in any form, such as a pharmaceutically acceptable salt thereof or a mixture of pharmaceutically acceptable salts thereof. Antibiotics can be prepared and administered via known routes of administration, and there are no particular restrictions.

[0169] Anti-VEGF drugs typically include biopharmaceuticals that target VEGF, such as ranibizumab, aflibercept, bevacizumab, and convercept.

[0170] Treatment method The compounds of this disclosure are useful as therapeutic agents for treating and / or preventing diseases or disorders associated with infection by the microorganism of the present application, such as Bacillus megatherium (e.g., eye infections, e.g., in the intraocular space). As shown in the Examples section, representative compounds of this disclosure exhibit strong activity in in vitro studies, such as killing or inhibiting representative microorganisms, such as Bacillus megatherium. Furthermore, the examples demonstrate that antibiotics such as vancomycin can reduce dorsenoid lesions induced by Bacillus megatherium by killing or inhibiting Bacillus megatherium in vivo, for example, in the rhesus monkey model of the present application.

[0171] Accordingly, in several embodiments, the Disclosure further provides methods for treating infections of the microorganisms of the Application, such as Bacillus megatherium, and for treating or preventing diseases or disorders associated with such infections (e.g., AMD), using the compounds of the Disclosure or the pharmaceutical compositions of the Application.

[0172] Unless otherwise specified, in any of the foregoing embodiments of this application, the infection may include, for example, an ocular infection in the intraocular space. Unless otherwise specified, in any of the foregoing embodiments of this application, the microorganism may include Bacillus megatherium. In some embodiments, the microorganism may include one or more selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae.

[0173] In several embodiments, the compounds of the present disclosure may be used to kill or inhibit the growth of the microorganism of the present application, such as Bacillus megatherium. In some embodiments, the compounds of the present disclosure may be used to treat or prevent AMD, such as dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), such as dry or wet age-related macular degeneration with soft drusen symptoms. The compounds of the present disclosure may be used alone, in combination with each other, or in combination with other antibiotics and / or anti-VEGF agents, as described in the present application.

[0174] In some embodiments, the Disclosure provides a method for killing or inhibiting the growth of a microorganism of the Application, such as Bacillus megatherium. In some embodiments, the method comprises contacting the microorganism with an effective amount of the compound of the Disclosure or the aforementioned pharmaceutical composition of the Application. In some embodiments, the contact may be in vitro, ex vivo, or in vivo.

[0175] In some embodiments, the Disclosure further provides methods for killing or inhibiting the growth of the microorganism of the Application, such as Bacillus megatherium, in subjects requiring such action. In some embodiments, the method includes administering to a subject one of the compounds of the Disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any subformula thereof, or any of compounds 1 to 8, or pharmaceutically acceptable salts or esters). Unless otherwise indicated, in any of the foregoing embodiments of the Application, the method may also include administering to a subject one of the compounds selected from compounds 1 to 8 or pharmaceutically acceptable salts or esters. Unless otherwise indicated, in any of the foregoing embodiments of the Application, the method may also include administering to a subject one of the pharmaceutical compositions that do not contain, or substantially contain, any of the compounds selected from compounds 1 to 8 or pharmaceutically acceptable salts or esters. In some embodiments, the compound or pharmaceutical composition is administered to a subject in an amount that effectively kills or inhibits the growth of microorganisms in the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract (e.g., intestines). In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject's eyes are infected with the microorganism of the Application, e.g., Bacillus megatherium. In some embodiments, the method further includes the step of the subject identifying, or having identified, the infected microorganism, e.g., Bacillus megatherium, e.g., in the intraocular space. In some embodiments, the subject is further administered an antibiotic and / or anti-VEGF agent, e.g., as described in the Application. In such embodiments, the antibiotic and / or anti-VEGF agent may be administered to the subject simultaneously with or sequentially in any order to the compound or pharmaceutical composition of the Disclosure.

[0176] In some embodiments, the Disclosure provides a method for treating or preventing AMD in a subject in need thereof. In some embodiments, the method includes administering to a subject a therapeutically effective dose of one of the compounds of the Disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V), any variant thereof, or any of compounds 1 to 8, or a pharmaceutically acceptable salt or ester. Unless otherwise indicated, in any of the foregoing embodiments of the Application, the method may also include administering to a subject a compound selected from compounds 1 to 8 or a pharmaceutically acceptable salt or ester. Unless otherwise indicated, in any of the foregoing embodiments of the Application, the method may further include administering to a subject a pharmaceutical composition which does not contain, or substantially contains, any compound selected from compounds 1 to 8 or a pharmaceutically acceptable salt or ester. In some embodiments, the method may further include administering to a subject an antibiotic and / or anti-VEGF agent, for example, as described in the Application. In some embodiments, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), for example, dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method further includes identifying, or having identified, that a subject is infected with the microorganism of the present invention, for example, Bacillus megatherium, in the intraocular space. In some embodiments, the subject is infected with the microorganism of the present invention, for example, Bacillus megatherium, in the intraocular space. In some embodiments, the method includes administering a compound or pharmaceutical composition to a subject in an amount that effectively kills or inhibits the growth of the microorganism of the present invention, for example, Bacillus megatherium, in the subject's eye (e.g., intraocular space), blood and / or gastrointestinal tract, for example, the intestine.

[0177] The administration of the present invention is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, topical, intraocular, intravitreous, transdermal, transpulmonary, inhaled, transbuccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrasacral, and parenteral. In some embodiments, administration may be oral, topical, intravitreous, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, administration is intravitreous.

[0178] The dosage and frequency of medication vary depending on several factors, such as the person being treated, the disease or disorder being treated and its severity, the composition of the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance, and whether or not other medications are being administered simultaneously.

[0179] extract In one embodiment, the present disclosure further provides extracts of several traditional Chinese medicines (TCMs) having antimicrobial activity. The term traditional Chinese medicine should be interpreted broadly to include both herbal and non-herbal traditional Chinese medicines, as described, for example, in the corresponding chapter of the Pharmacopoeia of the People's Republic of China (current edition). As will be described in detail in the Examples chapter, several TCMs have been found to be active against the representative microorganism of the present application, Bacillus megatherium. While some of the isolates derived from these TCMs have been further identified as being active against Bacillus megatherium, the extracts themselves are useful for the treatment of infections and related diseases or disorders of the microorganism of the present application, such as AMD.

[0180] Accordingly, in some embodiments, the present disclosure provides a method for treating or preventing AMD in a subject in need thereof, the method comprising the step of administering to a subject one or more TCM-derived extracts selected from licorice (e.g., Glycyrrhiza uralensis), pycnopilus (e.g., Cynanchum otophyllum), forsythia suspense, oyster shell (e.g., Citrus aurantium L.), rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch), citrus peel (e.g., Citrus reticulata Blanco), and citrus fruit (e.g., Panax notoginseng). In some embodiments, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen, and / or degraded drusen), for example, dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method further includes identifying, or having identified, that a subject is infected with the microorganism of the present invention, such as Bacillus megatherium, in the intraocular space, for example.

[0181] In some embodiments, the Disclosure provides a method for killing or inhibiting the growth of the microorganism of the Application in a subject requiring such treatment, or a method for treating an infection with the microorganism of the Application, such as Bacillus megatherium, the method being used with licorice (e.g., Glycyrrhiza The method comprises administering to a subject one or more TCM-derived extracts selected from (e.g., uralensis), (e.g., Cynanchum otophyllum), (e.g., Forsythia suspense), (e.g., Citrus aurantium L.), (e.g., Rehmannia glutinosa Libosch), (e.g., Citrus reticulata Blanco), and (e.g., Panax notoginseng). In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject's eye is infected with the microorganism of the application, e.g., Bacillus megatherium. In some embodiments, the method further comprises identifying, or having identified, that the subject is infected with the microorganism, e.g., Bacillus megatherium, for example, in the intraocular space. In some embodiments, for example, as described in this application, the subject is further administered an antibiotic and / or an anti-VEGF drug.

[0182] In some embodiments, the extract may be an extract of a single TCM. For example, in some embodiments, the method includes administering an extract of licorice (e.g., Glycyrrhiza uralensis) to a subject. In some embodiments, the method includes administering an extract of cypress (e.g., Cynanchum otophyllum) to a subject. In some embodiments, the method includes administering an extract of forsythia suspense to a subject. In some embodiments, the method includes administering an extract of kikoku (e.g., Citrus aurantium L.) to a subject. In some embodiments, the method includes administering an extract of rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch) and tangerine peel (e.g., Citrus reticulata Blanco) to a subject. In some embodiments, the method includes administering an extract of sanshichi (e.g., Panax notoginseng) to a subject.

[0183] In some embodiments, the extract may be an extract of a combination of two or more TCMs. For example, in some embodiments, the method includes administering to a subject an extract derived from two or more TCMs selected from licorice (e.g., Glycyrrhiza uralensis), pycnopilus (e.g., Cynanchum otophyllum), forsythia suspense, cinnamon (e.g., Citrus aurantium L.), rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch), citrus peel (e.g., Citrus reticulata Blanco), and citrus fruit (e.g., Panax notoginseng). In some embodiments, the method includes (a) licorice (e.g., Glycyrrhiza uralensis), pycnostem (e.g., Cynanchum otophyllum), forsythia (e.g., Forsythia suspense), cinnamon (e.g., Citrus aurantium L.), rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch), and dried tangerine peel (e.g., Citrus The method comprises the steps of (a) administering to a subject one TCM selected from (b) *Lycoperdon reticulata* and *Citrus umbellatus* (e.g., *Panax notoginseng*); and (b) administering to a subject an extract derived from one or more other TCMs. In some embodiments, the method comprises the steps of (a) independently administering to a subject one to seven (but not all) TCMs in any combination selected from *Licorice*, *Pachycarpus erythrosora*, *Forsythia suspensa*, *Hypochaeris erythrosora*, *Lycoperdon umbellatus*, *Citrus umbellatus*, and *Citrus umbellatus*, and optionally (b) administering to a subject an extract derived from one or more other TCMs.

[0184] The extracts of this application are usually prepared according to the general practice of TCM. See, for example, the Examples chapter. When two or more TCMs are used, the extract may be prepared by extracting each TCM (or any subgroup of TCMs) individually and then combining these extracts, or by extracting two or more TCMs simultaneously. Typically, the extract is an aqueous extract. In some embodiments, non-aqueous extracts are also useful. Note that for some TCMs, parts of multiple plants, such as leaves, stems, roots, fruits, seeds, etc., are useful. In the embodiments of this application, the extract is not limited to any particular part of the TCM plant when applied.

[0185] The extract of this application may exist or be administered in liquid, semi-solid, or solid form, or in any other form. For example, the extract may be administered as an aqueous solution, suspension, or emulsion. Alternatively, the extract may be manufactured into capsules, tablets, powders, etc., and administered accordingly, usually orally. The administration of the extract may follow typical practices relating to TCM and is not limited to a specific route of administration. The administration protocol, such as the amount and frequency, may be adjusted depending on several factors, such as the person being treated, the disease or disorder being treated and its severity, the composition of the extract it contains, the time of administration, the route of administration, the duration of treatment, the potency of the extract, its clearance, and whether or not another drug is being administered simultaneously. In some embodiments, the extract is administered in an amount that effectively kills or inhibits the growth of the microorganism of this application, such as Bacillus megatherium, in the subject, for example, the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, for example, the intestines.

[0186] antibiotics As discussed in this application, the present invention is in part based on the unexpected discovery that the intraocular environment is not sterile and that some intraocular microbiomes can be pathogenic to AMD. Therefore, any antibiotic, for example, those known in the art, can be used to treat infections of the microorganisms of the application and to treat or prevent AMD. Accordingly, in some embodiments, the disclosure further provides a method for killing or inhibiting the growth of the microorganisms of the application, for example Bacillus megatherium, a method for treating an infection of the microorganisms of the application (e.g., an eye infection, e.g., in the intraocular space), and / or a disease or disorder associated with the microorganism or infection, for example AMD, the method comprising the step of administering an effective dose of the antibiotic to the subject. In some embodiments, any commercially available antibiotic, for example, an antibiotic approved by the U.S. FDA, can be used. In some embodiments, the antibiotic may be characterized as a broad-spectrum antibiotic. In some embodiments, the antibiotic may be an antibiotic against Gram-positive bacteria. In some embodiments, the subject suffers from AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject has an eye infection, for example, an infection with one of the microorganisms of the Application, e.g., Bacillus megatherium. In some embodiments, AMD may be dry or wet age-related macular degeneration with drusen symptoms (including rigid drusen, soft drusen, mixed drusen and / or degraded drusen), e.g., dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method further includes identifying, or having identified, that the subject is infected with, for example, the microorganism of the Application, e.g., Bacillus megatherium, in the intraocular space. In some embodiments, the subject is infected with, for example, the microorganism of the Application, e.g., Bacillus megatherium, in the intraocular space. In some embodiments, for example, the subject is administered an anti-VEGF drug as described in the Application.

[0187] The compounds of this disclosure (see, for example, the chapter on compounds) typically possess antimicrobial activity and may therefore be used as antibiotics. However, the antibiotics described in this chapter may be independent of the compounds of this disclosure (for example, as defined in this application). In some embodiments, the antibiotic is also a compound of this disclosure. In some embodiments, the antibiotic is not a compound of this disclosure. In some embodiments, the antibiotic and the compounds of this disclosure are used in combination therapy, and they may be administered simultaneously (for example, as single dosage forms) or sequentially to the patient in need in any order.

[0188] In some embodiments, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or an azole antibiotic, or a combination thereof.

[0189] In some embodiments, the antibiotic is a β-lactam antibiotic, such as penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pivampicillin, pibmecillinum, ticarcillin, cephalosporins such as cephastril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapirin, ceph Atrazine, Cefazalur, Cefazedone, Cefazolin, Cepharazine, Cefuroxazine, Ceftezol, Cefaclor, Cephamandol, Cefmetazole, Cefonisid, Cefotetan, Cefoxitin, Cefprodil, Cefuroxime, Cefzonam, Cefcapene, Cefdaroxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefozidime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Cefthioflu, Cephthaloline, Ceftizoxime, Ceftriaxone, Cefope Lazon, ceftazidime, cefclizine, cefepime, ceffluprenum, cefoselis, cefozopran, cefpirome, cefquinome, ceftoviprole, cephthaloline, cefaclomedine, cephaloram, cephaparol, cefcanel, cefedrol, cefenpidone, cefetrizole, cefibitril, cefmatilen, cefmepidium, cefobesin, cefoxazole, cefrotil, cefsumide, cefuratime, ceftioxide, thienamicin derivatives, monobactam derivatives, β-lactamers Ze inhibitors, methoxypenicillins; aminoglycoside antibiotics, such as streptomycin, gentamicin, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribomycin, micronomisomycin, azithromycin, dibekacin, shisomycin, netylmycin, paromomycin, bramycin, etc.; tetracycline antibiotics, such as tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.Chloramphenicol antibiotics, e.g., chloramphenicol, thianphenicol, etc.; macrolide antibiotics, e.g., erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, medimycin, josamycin, azithromycin, clarithromycin, dilithromycin, roxithromycin, telithromycin, etc.; glycopeptide antibiotics, e.g., vancomycin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, e.g., norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; Nitroimidazole antibiotics, e.g., metronidazole, tinidazole, ornidazole; rifamycin antibiotics, e.g., rifampicin; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics: may include one or more of the following: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, and polymyxin B combinations, e.g., polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / gramicidin, etc.

[0190] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, salvarsan, azithromycin, azurocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cephalothin, cephamandol, cefazolin, cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprodil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, ceffuroxime, chloramphenicol, Cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dalfopristin, dapsone, daptomycin, dicloxacillin, zilithromycin, doripenem, doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, loracalbef, mafenide, meropenem, methoxypenicillin, metronidazole Zole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netylmycin, nitrofurantoin, oxacillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifamycin, rifapentin, rifaximin, roxithromycin, silver sulfadiazine, spectinomycin, streptomycin, sulba Tam, sulfacetamide, sulfadiazine, sulfamethizol, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavancin, telithromycin, temocillin, tetracycline, thianphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, trimethoprim, troreoandmycin, vancomycin, enoxacin, lomefloxacin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin,Moxifloxacin, ofloxacin, norfloxacin, cefotetan, cefonisid, cephaladine, cefapillin, cephalothin, cefmetazole, cefotaxime, moxalactam, cefepime, cephthaloline fosamil, ceftoviprole, dalbavancin, demeclocycline, metacycline, ertapenem, fidaxomicin, geldanamycin, harbimycin, posizolid, radezolid, Torezolid, Oritavancin, Spiramycin, Sulfadimethoxine, Sulfonamidochrysoidine, Gemifloxacin, Nadifloxacin, Trovafloxacin, Glepafloxacin, Sparfloxacin, Temafloxacin, Teixobactin, Malacidins, and combinations thereof may be selected.

[0191] In some embodiments, the antibiotic is administered in a dose that effectively kills or inhibits the growth of the microorganism of the present invention, such as Bacillus megatherium, in the subject, for example, the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, for example, the intestines.

[0192] Antibiotics may be in any form, for example, in the form of a corresponding pharmaceutically acceptable salt or a mixture of corresponding pharmaceutically acceptable salts. Antibiotics can be prepared and administered by known routes of administration, and are not particularly limited. In some embodiments, administration may be oral, topical, intravitreous, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, administration is intravitreous.

[0193] Medication protocols, such as dosage and frequency, vary depending on several factors, including the person being treated, the disease or disorder being treated and its severity, the composition of the antibiotic contained, the time of administration, the route of administration, the duration of treatment, the antibiotic's potency, its clearance, and whether or not other medications are being administered simultaneously.

[0194] Exemplary Alternative Embodiments In some embodiments, this disclosure relates to a method for creating a model and a model created by said method. In other embodiments, this application discloses a method for screening pharmaceuticals and pharmaceuticals identified by said method. In some embodiments, this disclosure relates to the use of microorganisms in model creation and pharmaceutical screening.

[0195] In one embodiment, the present application discloses a method for preparing a model, the method comprising the step of infecting a model carrier with a microorganism. The microorganism includes or consists of bacteria, archaea, protists, fungi, viruses, or a combination thereof. Preferably, the microorganisms include bacteria, and these bacteria belong to the genera Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospira, and Axylosa. It may also be one or more species selected from the genera Aquimarina, Achromobacter, Acidithiobacillus, Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus, Methanobrevibacter, Shigella, Frankia, Anaeroplasma, and Coprococcus.

[0196] In some preferred embodiments, the bacteria include Clostridium tetanus, Clostridium perfringens, Clostridium botulinum, Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, and Porphyromonas asacaroristica. asacharolytica), Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni jejuni), Campylobacter coli, Campylobacter seabirds, Campylobacter Uppsala, Campylobacter concisely, Campylobacter fitus, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontolyticus, Escherichia coli, Escherichia blattae, Escherichia fergusonii, Escherichia hermannii hermannii), Escherichia vulneris, Tissierella apical, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilence, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxydance ferrooxidans), Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikovi, Ruminococcus albus, Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella Shigella dysenteriae, Shigella flexneri, Shigella bogdii, Shigella sonnei, Frankiaceae, Streptomyces albusalbus), Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus It may also be one or more species selected from Russ licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas witchi, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0197] In some preferred embodiments, the bacteria include Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, and Cytophaga hutchin. It may also be one or more species selected from Bacillus sonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas witchi, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0198] In some preferred embodiments, the bacterium is one or more selected from Pseudomonas putida, Bacillus megatherium, and Propionibacterium acnes. In preferred embodiments, the bacterium is Bacillus megatherium.

[0199] In some preferred embodiments, the disclosure relates to a method for creating a model relating to cataracts (Cat), the method comprising the step of infecting a model carrier with one or more microorganisms selected from Pseudomonas mendocina, Chitococcus sedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, or Acidoborax ebreus.

[0200] In some preferred embodiments, the disclosure relates to a method for creating a model of age-related macular degeneration (AMD), the method comprising the step of infecting a model carrier with one or more microorganisms selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae.

[0201] In some preferred embodiments, the disclosure relates to a method for creating a model relating to glaucoma (GLA), the method comprising the step of infecting a model carrier with one or more microorganisms selected from Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, or Serratia marcescens.

[0202] In some preferred embodiments, the disclosure relates to a method for creating a model relating to Behçet's disease (BD), the method comprising the step of infecting a model carrier with one or more microorganisms selected from Sphingomonas witch, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruickii, or Meiothermus sylvanus (D).

[0203] In some preferred embodiments, the present disclosure relates to a method for creating a model for Vogt-Koyanagi-Harada syndrome (VKH), the method comprising the step of infecting a model carrier with one or more microorganisms selected from Escherichia coli, Mycococcus luteus, Bacillus subtilis, Corynebacterium auricum, or Finegordia magna.

[0204] The model carrier may include one or more of the following: humans, non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, body fluid cultures, cells, viruses, enzymes, and culture media. Non-human mammals may include any mammal used for laboratory, pet, or economic purposes. Exemplary non-human mammals include mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, monkeys, or non-human primates. Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, nose, and tongue. Tissues, tissue sections, and tissue extracts include tissues, tissue sections, or tissue extracts derived from any part of the subject or test animal. In some embodiments, tissues include the suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous humor, retina, choroid, optic nerve, lens, or iris of the subject. In some embodiments, tissue extracts include DNA, RNA, or proteins. In some embodiments, the body fluid includes lymph, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or urine. In some embodiments, the body fluid culture includes AH and VH cultures.

[0205] In another aspect, the present application discloses the use of microorganisms in the preparation of a model, specifically, the model being prepared by infecting a model carrier with microorganisms. The defined scope of microorganisms and model carriers is as described in the present application.

[0206] In a further embodiment, the present application discloses a model created by infecting a model carrier with a microorganism. The defined scope of the microorganism and model carrier is as described in the present application.

[0207] In a further embodiment, the present application discloses a method for screening pharmaceuticals, the method comprising the steps of (1) applying a pharmaceutical to a model and (2) analyzing the results. Preferably, the method comprises the steps of (1) creating a model by infecting a model carrier with a microorganism, (2) applying a pharmaceutical to the model, and (3) analyzing the results. Pharmaceuticals that kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects.

[0208] Microorganisms include or consist of bacteria, archaea, protists, fungi, viruses, or combinations thereof. Preferably, microorganisms include bacteria, which may be one or more species selected from the genera Clostridium, Acinetobacter, Streptococcus, Mannhemia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tisierella, Klebsiella, Porphyromonas, Azopira, Achimarina, Achromobacter, Acidothiobacillus, Burkholderia, Marinobacter, Treponema, Actisporandium, Vibrio, Ruminococcus, Metanobrevibuster, Sigella, Frankia, Aneroplasma, and Coprococcus.

[0209] In some preferred embodiments, the bacteria include Clostridium tetanus, Clostridium perfringens, and Clostridium botulinum. Idium botulinum), Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii Campylobacter junii), Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacharolytica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabirds, Campylobacter Uppsala, Campylobacter concisseri (conceally), Campylobacter fitus, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontolyticus, Escherichia coli Escherichia coli, Escherichia blattae, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris, Tissierella apical, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilence, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans thiooxidans), Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikovi, Ruminococcus albus, Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella boidii Shigella sonnei, Frankiaceae, Streptomyces albusalbus), Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus It may also be one or more species selected from Russ licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas witchi, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0210] In some preferred embodiments, the bacteria include Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, and Cytophaga hutchin. It may also be one or more species selected from Bacillus sonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas witchi, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0211] In some preferred embodiments, the bacteria may be one or more selected from Pseudomonas putida, Bacillus megatherium, and Propionibacterium acnes.

[0212] In a preferred embodiment, the bacterium is Bacillus megatherium.

[0213] The model carrier may be one or more of the following: humans, non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, body fluid cultures, cells, viruses, enzymes, and culture media. Non-human mammals include any mammal used for laboratory, pet, or economic purposes. Exemplary non-human mammals include mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, monkeys, or non-human primates. Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, nose, and tongue. Tissues, tissue sections, and tissue extracts include tissues, tissue sections, or tissue extracts derived from any part of the subject or test animal. In some embodiments, tissues include the suspensory ligament, ciliary body, ciliary muscle, vitreous humor, retina, choroid, optic nerve, lens, or iris of the subject. In some embodiments, tissue extracts include DNA, RNA, or proteins. In some embodiments, the body fluid includes lymph, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or urine. In some embodiments, the body fluid culture includes AH and VH cultures.

[0214] Pharmaceuticals may include one or more of the following: small molecule drugs, chemical drugs, large molecule drugs, biopharmaceuticals, or natural drugs (herbal medicines or herbal medicine extracts).

[0215] Preferably, the pharmaceutical product has a therapeutic effect on intraocular diseases or disorders, including age-related macular degeneration (AMD), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), uveitis, retinal diseases, dry keratoconjunctivitis, sympathetic ophthalmia, cataracts (Cat), conjunctivitis, meibomian gland cysts, glaucoma (GLA), and floaters.

[0216] Chemical drugs include: β-lactam antibiotics: penicillins, cephalosporins, β-lactamase inhibitors and methoxypenicillin; aminoglycoside antibiotics: streptomycin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribomycin and novobiocin; tetracycline antibiotics: tetracycline, oxytetracycline and chlortetracycline; chloramphenicol antibiotics: chloramphenicol and thianphenicol; macrolide antibiotics: erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, medimycin, josamycin and azithromycin; glycopeptide antibiotics: Lincomycin, norvancomycin, and teicoplanin; quinolone antibiotics: norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, and gatifloxacin; nitroimidazole antibiotics: metronidazole, tinidazole, and ornidazole; rifamycin antibiotics: rifampicin; echinocandin antibiotics, polyene antibiotics, pyrimidine antibiotics, allylamine antibiotics, azole antibiotics, and other antibiotics: fosfomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, or combinations thereof.

[0217] The biological drug may also be an antimicrobial peptide, which may include insect antimicrobial peptides: lepidopteran antimicrobial peptides, diptera antimicrobial peptides, coleoptera antimicrobial peptides, hymenoptera antimicrobial peptides and silkworm antimicrobial peptides; mammalian antimicrobial peptides: porcine antimicrobial peptides, sheep antimicrobial peptides, bovine antimicrobial peptides and human antimicrobial peptides; amphibian antimicrobial peptides: African clawed frog; antimicrobial peptides derived from fish, mollusks or crustaceans: leopard antimicrobial peptides, mussel antimicrobial peptides and shrimp antimicrobial peptides; bacterial antimicrobial peptides: bacitracin, gramicidin, polymyxin and nisin; plant antimicrobial peptides, or combinations thereof.

[0218] Natural medicines include Astragalus, Polygonatum, Angelica, Sanqi, Rhizoma Imperatae, Rhubarb Charcoal, Curcuma aromatica, Fritillary, Coix Seed, Pinellia, Calcined ancient ink, Salvia Miltiorrhiza, Arnebia euchroma, and Radix. Isatidis), Houttuynia, Honeysuckle, Rhizoma Coptis, Scutellaria, Dandelion, Purslane, Hawthorn, Isatidis Folium, Fructus Forsythiae, Herba Artemisiae Capillaris, Andrographis Paniculata Nees, Radix Bupleuri, Rhubarb, Euphorbia Humifusa, Stemonae, Garlic, Cortex Phellodendri, Eucommia, Cortex Fraxini, Fructus It may also contain extracts of or combinations of the following: Cnidii, Galla Chinensis, Viola yedoensis makino, Fructus Mume, Radix Glycyrrhizae, Pericarpium Granati, Schisandra chinensis, Spina Gleditsiae, Terminalia Chebula, Sophora flavescens, Cortex Pseudolaricis, Epimedium, Artemisia apiacea Hance.

[0219] The pharmaceuticals of this disclosure may be oral pharmaceuticals, injectable pharmaceuticals, or topical pharmaceuticals, and topical pharmaceuticals include mucosal agents, preferably eye drops.

[0220] The pharmaceutical products of this disclosure may be in the form of solutions, tablets, pills, capsules, injections, powders, injection powders, patches, codes, or mucosal administration preparations, preferably eye drops, eye ointments, or eye spray preparations.

[0221] In some preferred embodiments, the present disclosure relates to a method for screening pharmaceuticals for treating or preventing cataracts (Cat), the steps of which are as follows: (1) Create a model by infecting a model carrier with one or more microorganisms from the following: Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, or Acidovorax ebreus. (2) Apply pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having a therapeutic or prophylactic effect on Cat patients.

[0222] In some preferred embodiments, the present disclosure relates to a method for screening pharmaceuticals for treating or preventing age-related macular degeneration (AMD), the steps of which are as follows: (1) Create a model by infecting a model carrier with one or more microorganisms from among Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae. (2) Apply pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having a therapeutic or prophylactic effect on AMD patients.

[0223] In some preferred embodiments, the present disclosure relates to a method for screening pharmaceuticals for treating or preventing glaucoma (GLA), the steps of which are as follows: (1) Create a model by infecting a model carrier with one or more microorganisms from among Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, or Serratia marcescens. (2) Apply pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having a therapeutic or prophylactic effect on GLA patients.

[0224] In some preferred embodiments, the present disclosure relates to a method for screening pharmaceuticals for the treatment or prevention of Behçet's disease (BD), the steps of which are as follows: (1) Create a model by infecting a model carrier with one or more microorganisms from among Sphingomonas witch, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruickii, or Meiothermus silvanus (D). (2) Apply pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having a therapeutic or prophylactic effect on BD patients.

[0225] In some preferred embodiments, the present disclosure relates to a method for screening pharmaceuticals for the treatment or prevention of Vogt-Koyanagi-Harada syndrome (VKH), the steps of which are as follows: (1) Create a model by infecting a model carrier with one or more microorganisms from among Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, or Finegordia magna. (2) Apply pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having a therapeutic or prophylactic effect on VKH patients.

[0226] In a further embodiment, the present application discloses the use of microorganisms for screening pharmaceuticals, specifically the pharmaceutical screening steps being: creating a model by infecting a model carrier with microorganisms; applying the pharmaceutical to the model; and screening the therapeutic or prophylactic effect of the pharmaceutical. The defined scope of microorganisms, model carriers, and pharmaceuticals is as described above.

[0227] In a further embodiment, the present invention discloses a drug identified by the steps of creating a model by infecting a model carrier with a microorganism, applying a drug to the model, and screening for positive results of the drug. The defined scope of the microorganism and model carrier is as described above.

[0228] A positive result means that the identified drug can kill or inhibit microorganisms in the model. Exemplary Embodiments 1-25

[0229] Embodiment 1. A method for creating an intraocular disease or disorder model, comprising the step of infecting a model carrier with microorganisms.

[0230] Embodiment 2. In the method described in Embodiment 1, the microorganism includes bacteria, archaea, protists, fungi, viruses, or a combination thereof.

[0231] Embodiment 3. In the method described in Embodiment 1, the model carrier comprises one or more of the following: human, non-human mammal, organ, tissue, tissue section, tissue extract, body fluid, body fluid culture, cell, virus, enzyme, and culture medium.

[0232] Embodiment 4. In the method described in Embodiment 2, the microorganism includes one or more bacteria selected from the genera Clostridium, Acinetobacter, Streptococcus, Mannhemia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tisierella, Klebsiella, Porphyromonas, Azopira, Achimarina, Achromobacter, Acidothiobacillus, Burkholderia, Marinobacter, Treponema, Actisporandium, Vibrio, Ruminococcus, Metanoblewibuster, Sigella, Frankia, Aneroplasma, and Coprocococcus.

[0233] Embodiment 5. In the method described in Embodiment 4, the bacteria are Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter chalcoseticus, Acinetobacter ruffi, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus pyogenes, Porphyromonas asacaroristica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabird, Campylobacter u Psala, Campylobacter concisseri, Campylobacter fetus, Actinomyces islaeri, Actinomyces neslandii, Actinomyces odontrichus, Escherichia coli, Escherichia brattae, Escherichia fergusoni, Escherichia hermannii, Escherichia bruneris, Tissierella apial, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilense, Achromobacter, Thiobacillus dennitrificans, Thiobacillus ferrooxydance, Thiobacillus thiooxy Dans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hiojicentelli, Vibrio meschnikovii, Ruminococcus albus, Ruminococcus flavefaciens, Metanoblevibacter luminantium, Shigella shiga, Shigella flexneri, Shigella boidii, Shigella sonnei, Frankia, Streptomyces albus, Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xylosa Xidans, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium,It is one or more species selected from Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0234] Embodiment 6. In the method described in Embodiment 1, the intraocular disease or disorder is selected from cataract, age-related macular degeneration, glaucoma, Behçet's disease, Vogt-Koyanagi-Harada syndrome, or uveitis.

[0235] Embodiment 7. The method according to Embodiment 1, wherein the intraocular disease or disorder is a cataract, and the method includes the step of infecting a model carrier with one or more microorganisms selected from Pseudomonas mendocina, Chitococcus sedentarius, Alicyclifolius dennitrificans, Achromobacter xyloxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Sinorhizobium melilotii, or Acidoborax ebreus.

[0236] Embodiment 8. The method according to Embodiment 1, wherein the intraocular disease or disorder is age-related macular degeneration, and the method includes the step of infecting a model carrier with one or more microorganisms selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae.

[0237] Embodiment 9. The method according to Embodiment 1, wherein the intraocular disease or disorder is glaucoma, and the method includes the step of infecting a model carrier with one or more microorganisms selected from Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, or Serratia marcescens.

[0238] Embodiment 10. The method according to Embodiment 1, wherein the intraocular disease or disorder is Behçet's disease, and the method includes the step of infecting a model carrier with one or more microorganisms selected from Sphingomonas witch, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruickii, or Meiothermus sylvanus (D).

[0239] Embodiment 11. The method according to Embodiment 1, wherein the intraocular disease or disorder is Vogt-Koyanagi-Harada syndrome, and the method includes the step of infecting a model carrier with one or more microorganisms selected from Escherichia coli, Mycococcus luteus, Bacillus subtilis, Corynebacterium auricum, or Finegordia magna.

[0240] Embodiment 12. Use of microorganisms in the creation of intraocular disease or impairment models.

[0241] Embodiment 13. An eye disease model prepared by the method described in Embodiment 1.

[0242] Embodiment 14. Use of microorganisms in creating a model for screening ophthalmic drug.

[0243] Embodiment 15. In the use described in Embodiment 14, the pharmaceutical product includes one or more of the following: chemical pharmaceuticals, biopharmaceuticals, or natural pharmaceuticals.

[0244] Embodiment 16. In the use described in Embodiment 15, the chemical drug includes β-lactam antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, chloramphenicol antibiotics, macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics, rifamycin antibiotics, echinocandin antibiotics, polyene antibiotics, pyrimidine antibiotics, allylamine antibiotics, azole antibiotics, and other antibiotics or combinations thereof.

[0245] Embodiment 17. In the use described in Embodiment 15, the biopharmaceutical is an antimicrobial peptide.

[0246] Embodiment 18. In the use described in Embodiment 15, the natural medicinal product includes Astragalus membranaceus, Osmanthus chinensis, Angelica acutiloba, Sansi, White Root, Rhubarb, Turmeric, Fritillaria thunbergii, Coix seed, Pinellia ternata, Magnolia lilac, Salvia miltiorrhiza, Scutellaria baicalensis, Scutellaria baicalensis, Prunus serrulata, Pachycarpus fortunei, Prunus jamasakura, Panax jasminoides, Forsythia suspensa, Andrographis paniculata, Bupleurum falcatum, Rhubarb, Sichuan rhizome, Stewartia pseudoacacia, Southern bayberry, Phellodendron bark, Eucommia ulmoides, Cymbidium goeringii, Scutellaria baicalensis, Eucommia ulmoides, Cymbidium goeringii, Scutellaria baicalensis, Eucommia ulmoides, Licorice, Amomum erythrorhizon, Schisandra chinensis, Sophora japonica, Quercus dentata, Sophora japonica, Cinnamomum asiaticum, Epimedium grandiflorum, Licorice, Acorus calamus Parmesan, Schisandra chinensis, Quercus dentata, Sophora japonica, Cinnamomum asiaticum, Epimedium grandiflorum, Licorice, extracts thereof, or combinations thereof.

[0247] Embodiment 19. In the use described in Embodiment 14, the microorganisms include bacteria, archaea, protists, fungi, viruses, or combinations thereof.

[0248] Embodiment 20. In the use described in Embodiment 19, the microorganism includes one or more bacteria selected from the genera Clostridium, Acinetobacter, Streptococcus, Mannhemia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tisierella, Klebsiella, Porphyromonas, Azopira, Achimarina, Achromobacter, Acidothiobacillus, Burkholderia, Marinobacter, Treponema, Actisporandium, Vibrio, Ruminococcus, Metanobrevibuster, Sigella, Frankia, Aneroplasma, and Coprocococcus.

[0249] Embodiment 21. In the use described in Embodiment 20, the bacteria are Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter chalcoseticus, Acinetobacter ruffi, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus pyogenes, Porphyromonas asacaroristica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabird, Campylobacter Uppsala, Campylobacter concisseri, Campylobacter fetus, Actinomyces islaeri, Actinomyces neslandii, Actinomyces odontrichus, Escherichia coli, Escherichia blattae, Escherichia fergusoni, Escherichia hermannii, Escherichia brunellis, Tissierella apial, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilense, Achromobacter, Thiobacillus dennitrificans, Thiobacillus ferrooxydance, Thiobacillus thiooxydance Sydans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hiojicentelli, Vibrio meschnikovii, Ruminococcus albus, Ruminococcus flavefaciens, Metanoblevibacter luminantium, Shigella shiga, Shigella flexneri, Shigella boidii, Shigella sonnei, Frankia, Streptomyces albus, Pseudomonas mendocina, Chitococcus cedentarius, Alicyclifolius dennitrificans, Achromobacter xy Roxidance, Sphingobium chaponicum, Mycobacterium abscesses, Arthrobacter aurecens, Prevotella dentalis, Cinorhizobium melilotii, Acidoborax ebreus, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium,It is one or more species selected from Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter chalcoseticus, Comamonas testosterone, Mycobacterium kansasi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescein, Ralstonia picketti, Lactobacillus crispatus, Burkholderia multiboran, Lactobacillus delbruckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegordia magna.

[0250] Embodiment 22. In the use described in Embodiment 14, the eye disease is selected from cataracts, age-related macular degeneration, glaucoma, Behçet's disease, Vogt-Koyanagi-Harada syndrome, or uveitis.

[0251] Embodiment 23. A method for screening pharmaceuticals, comprising the steps of (1) applying the pharmaceutical to the model described in Embodiment 13, and (2) analyzing the results.

[0252] Embodiment 24. In the method described in Embodiment 23, the pharmaceutical product includes one or more of the following: a chemical pharmaceutical product, a biopharmaceutical product, or a natural pharmaceutical product.

[0253] Embodiment 25. A pharmaceutical product identified by the method described in Embodiment 23. Exemplary additional embodiments B1-B104 This disclosure further provides the following additional exemplary embodiments B1 to B104.

[0254] Embodiment B1. A method for treating or preventing age-related macular degeneration (AMD) in a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt or ester, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or ester. JPEG2026086398000094.jpg4565In formula, Cy 1 and Cy 2 Each of these is independently a substituted cycloalkyl ring (e.g., C 3-7 Cycloalkyl rings), substituted heterocycles (e.g., 4-7 membered heterocycles), substituted aromatic rings (e.g., C 6-10 Aromatic ring) or a substituted heteroaromatic ring (e.g., a 5-10 member heteroaromatic ring), L and L ’ Each is independently either empty or ringer. L 2 C may be empty or substituted. 1-6 Alkylene group, substituted KilC 1-6 Heteroalkylene group, optionally substituted C 2-6 Alkenylene group, may be substituted C 2-6 Alkynylene group, substituted or C 3-6 A cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4-7 membered heterocyclylene group. W is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or The file is JPEG2026086398000095.jpg1818, Here, R 1 and R 1a Each of these is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group. R 3 and R 4 These are, independently, hydrogen and -COR 2b , -SO2R 5b , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 3-6 A cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5 or 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 3 and R 4 These, together with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group. R 2 , R 2a , R 2b , R 5 , R 5a and R 5b These are, independently, hydrogen, -OH, and -NR. 3e R 4e , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, and R 3a , R 3b , R3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e These are, independently, hydrogen and substituted C. 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7-membered heterocyclic group, or R 3a and R 4a , R 3b and R 4b , R 3c and R 4c , R 3d and R 4d Or R 3e and R 4e These, along with the atoms to which they are bonded, form a substituted 4-7 membered heterocyclic group.

[0255] Embodiment B2. In the method described in Embodiment B1, in formula I, Cy 1 and Cy 2 C may be substituted for at least one of the following 6-10 It is an aromatic ring or a substituted 5-10 membered heteroaromatic ring.

[0256] Embodiment B3. In the method described in Embodiment B1, the compound of formula I has formula I-1. JPEG2026086398000096.jpg5070, During the ceremony, Ar 1 and Ar 2 Each of these can be substituted independently of C. 6-10 It is an aromatic ring or a substituted 5-10 membered heteroaromatic ring.

[0257] Embodiment B4. In the method described in Embodiment B3, Ar in formula I-1 1 and Ar 2 Each of these is independently a substituted benzene ring or a substituted 5- or 6-membered heteroaromatic ring.

[0258] Embodiment B5. In the method described in Embodiment B3, Ar in formula I-1 1 and Ar 2 Each of these is independently a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring.

[0259] Embodiment B6. In the method described in Embodiment B1, the compound of formula I has formula I-2. JPEG2026086398000097.jpg4880, During the ceremony, m is 0, 1, 2, or 3. R 10 Each time it appears, it independently emits halogen, -L 2’ -W ’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 10 , or one R 10 and L or L ’ These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. Here, L 2’ and W ’ These are L 2And has the definition in embodiment B1 of W, and -L 2’ -W ’ Each time they appear, they are chosen independently.

[0260] Embodiment B7. In the method described in Embodiment B6, Cy in formula I-2 1 is a substituted benzene ring, a substituted thiophene ring, a substituted furan ring, a substituted pyridine ring, or a substituted pyrimidine ring.

[0261] Embodiment B8. In the method described in Embodiment B6, Cy in formula I-2 1 C may be substituted. 3-6 The heterocycle is a cycloalkyl ring or a substituted 4-7 heterocycle, the heterocycle having one or two cycloheteroatoms independently selected from N, O, and S.

[0262] Embodiment B9. In the method described in Embodiment B6, the compound of formula I-2 has formula I-3. JPEG2026086398000098.jpg49118, During the ceremony, n is 0, 1, 2, or 3. R 11 Each time it appears, it independently emits halogen, -L 2’ -W ’ , substitution may be C 1-6 Alkyl alkyl group, may be substituted C 2-6 Alkenyl group, substitution in Container C 2-6 Alkynyl group, substituted KiC 1-6 Alkoxy group, substituted KarC 3-6 Cycloalkyl groups, may be substituted C 3-6 A cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5 or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or two adjacent R groups 11 , or one R 11 and L or L ’These, together with the atoms to which they are bonded, form a substituted cycloalkyl group, heterocyclic group, aryl group, or heteroaromatic ring. Here, L 2’ and W ’ These are L 2 and has the definition in embodiment B1 of W, and -L 2’ -W ’ Each time they appear, they are chosen independently.

[0263] Embodiment B10. In the method described in any one of Embodiments B1 to B9, L and L in formula I ’ These are, independently, empty, -C(O)-, and C which may be substituted. 1-4 Alkylene group, substituted KilC 2-4 Alkenylene group, -O-, -S-...

Claims

1. Step a) involves culturing microorganisms in a suitable medium in the presence of the test compound, Step b) measuring the growth of the microorganism in the culture medium in the presence of the test compound, and optionally A screening method comprising step c) identifying candidate therapeutic agents that inhibit the growth of the microorganism compared to a control, A screening method comprising the microorganisms, including species that are concentrated in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of subjects suffering from age-related macular degeneration (AMD) compared to healthy subjects.

2. The screening method according to claim 1, wherein the microorganisms include one or more species selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

3. The screening method according to claim 1, wherein the microorganisms include Bacillus megatherium and / or Pseudomonas putida.

4. The screening method according to claim 1, wherein the microorganism comprises a mixture of microbial species, and the microbial species are substantially similar to those observed in the aqueous humor, vitreous fluid and / or soft drusen of a subject suffering from age-related macular degeneration.

5. The screening method according to claim 1, wherein the microorganisms are partially or entirely derived from the aqueous humor and / or vitreous fluid of a subject suffering from age-related macular degeneration.

6. A screening method according to any one of claims 1 to 5, wherein the multiple test compounds include at least one test compound that is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism.

7. The screening method according to claim 6, wherein the test compound is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline.

8. The screening method according to any one of claims 1 to 7, wherein the identification includes the identification of a candidate therapeutic agent that prevents visible growth of the microorganism at or below the maximum test concentration.

9. The screening method according to any one of claims 1 to 7, wherein the identification includes the identification of a candidate therapeutic agent that prevents the formation of visible colonies of the microorganism at or below the maximum test concentration.

10. Step a) to determine, or have determined, one or more microbial species that are concentrated in the intraocular space of subjects with age-related macular degeneration (AMD) compared to healthy subjects, Step b) culturing microorganisms containing at least one of the microbial species to be concentrated in a suitable medium in the presence of the test compound, Step c) measuring the growth of the microorganism in the culture medium in the presence of the test compound, and optionally A screening method comprising step d) identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control.

11. The screening method according to claim 10, wherein the microorganism comprises a mixture of microbial species, and the microbial species are substantially similar to those observed in the aqueous humor, vitreous fluid and / or soft drusen of a subject suffering from age-related macular degeneration.

12. The screening method according to any one of claims 1 to 11, wherein the subject is a human subject.

13. A method for creating an animal model, comprising introducing microorganisms and / or inactivated proteins derived from such microorganisms into the intraocular space of an animal's eye, A method for creating an animal model in which the microorganisms include species that are concentrated in the intraocular space of subjects suffering from age-related macular degeneration (AMD) more than in healthy subjects.

14. The method according to claim 13, wherein the microorganisms include one or more selected species such as Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

15. The method according to claim 13, wherein the microorganism includes Bacillus megatherium and / or Pseudomonas putida.

16. The method according to claim 13, wherein the microorganism comprises a mixture of microbial species, and the microbial species are substantially similar to those observed in the aqueous humor, vitreous fluid and / or soft drusen of subjects suffering from age-related macular degeneration.

17. The method according to claim 13, wherein the microorganisms are derived from the aqueous humor and / or vitreous fluid of a subject suffering from age-related macular degeneration, in part or in whole.

18. The method according to any one of claims 13 to 17, wherein the animal is a primate other than a human (for example, a monkey).

19. The method according to any one of claims 13 to 17, wherein the animal is not a rhesus macaque.

20. The method according to any one of claims 13 to 19, wherein the microorganism and / or an inactivated protein derived from the microorganism is injected into the subretinal space of the animal.

21. The method according to any one of claims 13 to 20, wherein dorsenoid lesions are induced, for example, in the retinal tissue of the animal by injecting the microorganism and / or an inactivated protein derived from the microorganism.

22. The method according to any one of claims 13 to 21, wherein drusen-like nodules are induced, for example, beneath the retinal pigment epithelium layer in the eye of the animal, by injection of the microorganism and / or an inactivated protein derived from the microorganism.

23. The method according to any one of claims 13 to 22, wherein pyroptosis of retinal pigment epithelial cells in the eye of the animal is induced, for example, by injecting the microorganism and / or an inactivated protein derived from the microorganism.

24. The method according to any one of claims 13 to 23, wherein injecting the microorganism and / or an inactivated protein derived from the microorganism induces activation of the complement system and / or inflammation, for example, increased expression of C5A, CFH, caspase 1, and NLRP3 proteins, in the eye of the animal.

25. The method according to any one of claims 13 to 24, wherein the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of the animal is induced by injecting the microorganism and / or an inactivated protein derived from the microorganism.

26. An animal model prepared by the method described in any one of claims 13 to 25.

27. Step a) administering the test compound to the animal model described in claim 26, Step b) to determine the severity of one or more symptoms of eye disease after administration, and optionally A screening method comprising step c) identifying a candidate therapeutic agent that alleviates at least one of the aforementioned symptoms compared to a control.

28. The screening method according to claim 27, wherein the test compound is administered orally, topically, intravitreally, intramuscularly, subcutaneously, or intravenously.

29. The screening method according to claim 27 or 28, wherein the identification comprises the identification of a candidate therapeutic agent, compared to a control, the candidate therapeutic agent may: a) reduce dorsenoid lesions in the retinal tissue of the animal, b) reduce drusen-like nodules beneath the retinal pigment epithelial layer in the eye of the animal, c) reduce pyroptosis of retinal pigment epithelial cells in the eye of the animal, d) reduce complement system activation and / or inflammation in the eye of the animal, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins, e) reduce the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of the animal, or f) any combination of a) to e).

30. The screening method according to any one of claims 27 to 29, wherein the identification includes the identification of a candidate therapeutic agent, and compared to a control, the candidate therapeutic agent kills or inhibits the growth of the microorganisms in the eye (e.g., intraocular space or cavity), blood and / or gastrointestinal tract, e.g., the intestine, of the animal model.

31. The screening method according to any one of claims 27 to 30, wherein the test compound has been pre-screened as being able to effectively inhibit the growth of the microorganism.

32. The use of an effective dose of antibiotics in the treatment or prevention of AMD in the subject, for example, when the subject is identified as being infected in the intraocular space with one or more species selected from among Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

33. The use of effective doses of antibiotics in the treatment of drusen symptoms (e.g., soft drusen) in subjects requiring such treatment.

34. The use of effective doses of antibiotics in subjects requiring it for dorsenoid lesions, drusen-like nodules, pyroptosis of retinal pigment epithelial cells, activation and / or inflammation of the ocular complement system, and / or decreased secretion of active IL-1β and / or IL-18 by ocular retinal pigment epithelial cells.

35. (a) The subject has AMD (e.g., dry AMD or wet AMD), (b) The subject has soft drusen deposits between the retinal pigment epithelium (RPE) and Bruch's membrane, and / or has retinal pigment changes in the macula, (c) The subject has one or more species in the intraocular space that are more concentrated in the intraocular space of AMD patients than in healthy subjects, or (d) The subject has Staphylococcus epidermidis, Pseudomonas e in the intraocular space The use according to claim 33 or 34, wherein the organism is infected with one or more species selected from Luginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

36. The steps include obtaining a sample from aqueous humor or vitreous fluid of a subject selected from a subject suffering from the aforementioned eye disease, a family member or close genetic relative of a subject suffering from the aforementioned eye disease, or a deceased subject known to have the aforementioned eye disease, The process involves culturing one or more organisms from the aforementioned samples under conditions that mimic the space inside the human eye or in cooked meat medium to produce one or more cultures, The steps include adding the aforementioned compound or combination of compounds to one or more cultures, A method for screening the effectiveness of a compound or combination of compounds for the treatment or prevention of an eye disease, comprising the step of determining whether the compound or combination of compounds reduces the growth of one or more cultures or their population, The aforementioned eye disease is age-related macular degeneration (AMD), method.

37. The method according to claim 36, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, and combinations thereof.

38. The method according to any one of claims 36 to 37, further comprising the step of identifying a compound or combination of compounds that reduces the growth or population of one or more cultures in vitro, based on the aforementioned determination result.

39. A screening method for the effectiveness of compounds or combinations of compounds for the treatment or prevention of age-related macular degeneration (AMD), A step of producing one or more cultures by culturing one or more organisms under conditions that mimic the space inside the human eye or in cooked meat medium, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae and combinations thereof, The steps include adding the aforementioned compound or combination of compounds to one or more cultures, A method comprising the step of determining whether the compound or combination of compounds reduces the growth of one or more cultures or the population thereof.

40. The method according to claim 39, further comprising the step of identifying a compound or combination of compounds that reduces the growth or population of one or more cultures in vitro, based on the determination result.

41. A method for producing a mammalian model of age-related macular degeneration (AMD), comprising the step of introducing one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms into the eye of a mammal to produce the mammalian model.

42. The method according to claim 41, further comprising the step of monitoring the onset and progression of one or more markers of AMD.

43. The method according to claim 41 or 42, further comprising the step of introducing one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms into the mammal in order for it to develop a dorsenoid lesion, and then allowing a sufficient amount of time to pass.

44. The method according to any one of claims 41 to 43, wherein the step of monitoring the onset and progression of one or more markers of the eye disease includes monitoring the inflammatory response of the eye of the mammal.

45. The method according to any one of claims 42 to 43, wherein the step of monitoring the onset and progression of one or more markers of the eye disease includes monitoring the onset or progression of dorsenoid lesions.

46. The method according to any one of claims 41 to 45, wherein the introduction of the one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms comprises intraocular injection of the one or more microorganisms and / or one or more inactivated proteins of the one or more microorganisms.

47. The method according to any one of claims 41 to 46, wherein the mammal is a primate other than a human.

48. The method according to claim 47, wherein the mammal is a rhesus macaque.

49. The method according to any one of claims 41 to 48, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, and combinations thereof.

50. A screening method for the effectiveness of compounds or combinations of compounds for the treatment or prevention of age-related macular degeneration (AMD), The steps of administering the compound or combination of compounds to a mammalian model according to any one of claims 41 to 49, A screening method comprising the step of determining whether the compound or combination of compounds effectively reduces or prevents one or more symptoms of AMD.

51. The method according to claim 50, wherein the compound or a combination of compounds is administered after a dorsenoid lesion occurs in the mammalian model.

52. The method according to any one of claims 50 to 51, wherein administration comprises injecting the compound or combination of compounds into the eye of the mammalian model.

53. The method according to claim 52, wherein the injection includes an intraocular injection.

54. The method according to any one of claims 50 to 53, wherein the one or more symptoms are selected from the group consisting of the development of dorsenoid lesions, the growth or loading of microorganisms, the generation of inflammatory molecules or markers, and combinations thereof.

55. The use of a pharmaceutical composition comprising a therapeutically effective amount of a compound, glycoside (e.g., formula V), or pharmaceutically acceptable salt or ester of formula I (e.g., formula I-1, formula I-2, formula I-3, formula I-4, formula I-5), formula II (e.g., formula II-1, formula II-2, formula II-3, formula II-4, formula II-5, formula II-6, formula II-7, formula II-8, formula II-9, formula II-10), formula III (e.g., formula III-1, formula III-2, formula III-3), formula IV-1 or IV-2 (e.g., formula IV-3, formula IV-4, formula IV-5, formula IV-6), a pharmaceutically acceptable salt or ester of said compound or pharmaceutically acceptable salt or ester in a subject requiring such use, The aglycone of the glycoside is a phenol compound, a flavonoid, a coumarin, a benzoic acid, or a sterol, and formulas I, II, III, IV-1, IV-2, V and their sub-formulas are as defined herein.

56. The use of a pharmaceutical composition comprising a compound selected from compounds 1 to 8 in a therapeutically effective amount, a pharmaceutically acceptable salt or ester, or the compound or a pharmaceutically acceptable salt or ester, in the treatment or prevention of age-related macular degeneration (AMD) in a subject requiring such treatment, The compounds 1 to 8 have the following chemical structures. １、 ２、 ３、 ４、 ５、 ６、 7 and ８

57. The use according to claim 55 or 56, wherein the subject is identified, for example, as having a microbial infection in the intraocular space.

58. The use according to claim 57, wherein the microorganism includes Bacillus megatherium.

59. The use according to claim 57, wherein the microorganism includes one or more selected from Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

60. The use according to any one of claims 55 to 59, wherein the compound or a pharmaceutically acceptable salt or ester or the pharmaceutical composition is administered to the subject in an amount effective in killing or inhibiting the growth of the microorganisms in the subject's eyes (e.g., intraocular space), blood and / or gastrointestinal tract, such as the intestines.

61. The use according to any one of claims 55 to 60, wherein the pharmaceutical composition is administered orally.

62. The use of the pharmaceutical composition according to any one of claims 55 to 61, wherein the pharmaceutical composition is administered topically, intravitreously, intramuscularly, subcutaneously, or intravenously.

63. Use of an effective amount of antibiotic or pharmaceutically acceptable salt in a subject requiring its use for the killing or inhibition of the growth of microorganisms such as Bacillus megatherium, for example, in the treatment of microbial infections (e.g., eye infections, e.g., in the intraocular space) and / or in the treatment or prevention of age-related macular degeneration (AMD).

64. The use according to claim 63, wherein the subject is identified as being infected with a microorganism selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae in the intraocular space.

65. The use according to claim 64, wherein the microorganism includes Bacillus megatherium.

66. The use according to claim 64 or 65, wherein the amount of the antibiotic or pharmaceutically acceptable salt is effective in killing or inhibiting the growth of the microorganisms in the subject's eye (e.g., intraocular space), blood and / or gastrointestinal tract, such as the intestine.

67. The use of a therapeutically effective amount of extract in the treatment of microbial infections (e.g., eye infections, e.g., in the intraocular space) and / or in the treatment or prevention of age-related macular degeneration (AMD) in subjects requiring such treatment, The aforementioned extract is an extract derived from one or more TCMs selected from licorice (e.g., Glycyrrhiza uralensis), pycnopilus (e.g., Cynanthum otophyllum), forsythia suspense, cinnamon (e.g., Citrus aurantium L.), rehmannia glutinosa (e.g., Rehmannia glutinosa Libosch), citrus peel (e.g., Citrus reticulata Blancco), and citrus fruit (e.g., Panax notoginseng), for use.

68. The use according to claim 67, wherein the subject is identified as being infected with a microorganism selected from, for example, Staphylococcus epidermidis, Pseudomonas erginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae in the intraocular space.

69. The use according to claim 68, wherein the microorganism includes Bacillus megatherium.

70. The use according to claim 68 or 69, wherein the amount of the extract is effective in killing or inhibiting the growth of the microorganisms in the subject's eyes (e.g., intraocular space), blood, and / or digestive tract, such as the intestines.

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