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

Abstract

To provide screening methods and animal models related to intraocular diseases such as age-related macular degeneration (AMD), for example, for identifying candidate therapeutics for treating or preventing eye diseases, such as AMD.SOLUTION: Provided herein are compounds / compositions that are useful for killing or inhibiting the growth of a microorganism, such as Bacillus megaterium. Further provided are methods of using the compounds / compositions for treating infections with a microorganism, such as Bacillus megaterium, and for treating or preventing diseases or disorders associated with such infections, such as AMD.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application is filed on January 7, 2019, with International Application No. PCT / CN2019 / 070 572, International Application No. PCT / CN2019 / 084 filed on April 25, 2019 369, and Chinese Patent Application No. 201811351 filed on November 14, 2018 No. 660.9, the disclosures of which are incorporated herein by reference in their entirety. is incorporated by and for all purposes.

[0002] The present invention relates generally to the field of ophthalmic disease diagnosis and treatment, and more particularly to screening The present invention relates to methods for screening, animal models, and methods for treating or preventing ocular diseases or disorders. In some embodiments, the present disclosure further relates to a subject, e.g., a human patient or a vertebrate, e.g., a dog, cat, horse, or The present invention relates to compounds, compositions, and methods for treating and / or preventing age-related macular degeneration (AMD) in monkeys. and methods. [Background technology]

[0003] The eyes are the window to the soul. People use their eyes every day. However, the eye is very fragile. Various factors can cause eye discomfort or lesions. Common eye diseases include conjunctivitis and dry eye syndrome, as well as more serious intraocular diseases. or disorders include cataracts (CAT), age-related macular degeneration (AMD), glaucoma (GLA), These include BD, Vogt-Koyanagi-Harada syndrome (VKH), and uveitis. do.

[0004] Among older adults, age-related macular degeneration (AMD) is the leading cause of irreversible vision loss worldwide. This is due to the presence of a confluent soft tissue deposited between the retinal pigment epithelium (RPE) and Bruch's membrane. characterized by retinal drusen and / or early-stage macular pigmentary changes (intermediate AMD) In later stages, advanced AMD is characterized by geographic atrophy of the macula (dry AMD) and choroidal hemorrhage of the macula. AMD is characterized by two major subtypes: neovascular (wet) AMD and non-neovascular (wet) AMD. It has been used to control wet AMD, but there are currently no approved treatments for dry AMD. There was no therapy.

[0005] The mechanism of AMD development involves both genetic and environmental factors. In the pathology of glaucoma, the environmental factors that cause local inflammation and lead to early soft drusen formation are unclear. Complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and HtrA receptor Many alterations in loci associated with AMD susceptibility, including HTRA1 (Hypothyroidism) These findings suggest that AMD may be an inflammatory disease.

[0006] Currently, in the pathology of AMD, it causes local inflammation and leads to early soft drusen Environmental factors are unknown. Evaluating intraocular diseases or disorders in a subject, e.g., a mammal or human, There is a need for improved compositions and methods for treating or preventing inflammatory bowel diseases. The present disclosure addresses this need. , and other related needs. Summary of the Invention [Problem to be solved by the invention]

[0007] In some embodiments, the present invention provides screening methods for multiple types of ocular diseases, e.g., human ocular diseases. These screening methods and animal models are based in part on It has been reported that the intraocular environment is not sterile, and that some intraocular microflora, e.g., Bacillus megaterium, This is based on the unexpected discovery that cerebrospinal fluid may be a causative factor in several eye diseases, including AMD. do. [Means for solving the problem]

[0008] In some embodiments, the present invention provides a candidate therapeutic agent for treating or preventing an ocular disease, such as AMD. The present invention provides a screening method for identifying a cellular component of a cell that is a target of cellular proliferation, e.g., in a culture dish. In vitro screening methods or in vivo screening methods using, for example, the animal models described herein It may also be a boss cleaning method.

[0009] In some embodiments, the present invention involves culturing a microorganism in an appropriate medium in the presence of a test compound. a) measuring the growth of the microorganism in the medium in the presence of the test compound; and optionally, a candidate treatment that inhibits growth of said microorganism relative to a control. and c) identifying the agent. In this study, microorganisms were more likely to inhabit the intraocular space of subjects with ocular disease (e.g., Aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, optic nerve The eye diseases include age-related macular degeneration (AMD), vitreous leukemia (VELG), and vitreous leukemia (VLD). Buchett's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vo The following are selected from the group consisting of gt, Koyanagi-Harada syndrome (VKH), and combinations thereof. In some embodiments, the subject is a human subject. Treating diseases such as AMD, BD, Cat, EOS, GLA, VKH, or a combination thereof or preventive candidate therapeutic agents are identified.

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

[0011] Candidate therapeutic agents for treating or preventing other eye diseases such as BD, Cat, EOS, GLA, and VKH The screening method to identify leukemia is similar to that described for AMD, but As detailed in the application, different microorganisms are used. For example, in the case of BD, the presence of test compounds is monitored. The microorganisms cultivated under the conditions of sphingomonas are usually Sphingomonas wichii. wittichii, Klebsiella pneumoniae umoniae), Pseudomonas fluorescens (Pseudomonas fl uorescens), Ralstonia picketii tii), Lactobacillus crispa tus), Burkholderia multivorans (Burkholderia multiv orans), Lactobacillus delbricki brueckii), and Meiothermus sylvanus (Meiothermus si In the case of Cat. The microorganism cultivated in the presence of the compound is usually Pseudomonas mendocina. nas mendocina), Kytococcus sedentarius (Kytococcus sedentarius, Alicycliphilus denitrificans (Alicyc liphilus denitrificans), Achromobacter xyloxidans Achromobacter xylosoxidans, Sphingobium sphingobium Sphingobium japonicum, Mycobacterium a Mycobacterium abscessus, Arthrobacter a Arthrobacter aurescens, Prevotella dentalis Squirrel (Prevotella dentalis), Sinorhizobium meliloti (Si norhizobium meliloti), and Acidovorax ebreuthus (A The compound may contain one or more species selected from the group consisting of GLA, GLA-like compounds ... In this case, the microorganism to be cultured in the presence of the test compound is usually Acinetobacter baumannii (A Acinetobacter baumannii), Acinetobacter calcoacetica Acinetobacter calcoaceticus, Comamonas test Comamonas testosteroni, Mycobacterium kaempferi Mycobacterium kansasii, Bacillus thuringiensis sis (Bacillus thuringiensis), Citrobacter koseri (C itrobacter koseri), Diadobacter fermentans (Dya dobacter fermentants), and Serratia marcescens (Ser VKH may contain one or more species selected from the group consisting of VKH, VKH and VKH. In this case, the microorganism to be cultured in the presence of the test compound is usually Escherichia coli. coli), Micrococcus luteus , Bacillus subtilis, Corynebacterium auriculosus Corynebacterium aurimucosum and Finegoldii Finegoldia magna (Finegoldia magna) In some embodiments, the microorganisms used in the screening method are a mixture of microbial species. wherein the microbial species is BD, Cat, EOS, GLA or VKH, respectively. Substantially similar to that observed in the aqueous humor and / or vitreous humor of affected subjects In some embodiments, the microorganisms used in the screening method are partially or completely The aqueous humor and / or nitric oxide of subjects suffering from BD, Cat, EOS, GLA or VKH, respectively. It may also be derived from fetal body fluids.

[0012] The screening methods of the present application do not involve the detection of any particular test compound or any type of test compound. The present application describes several exemplary test compounds. The screening method of the present application may be used in low-throughput, medium-throughput, or high-throughput assays. A parallel test of multiple test compounds may be carried out as needed. The identification in the cleaning method is also not limited to any particular technique. In some embodiments, identification is of candidates that prevent visible growth of the microorganism at or below the maximum test concentration. In some embodiments, the identification includes identifying a therapeutic agent. This includes identifying candidate therapeutic agents that prevent recognizable colonization.

[0013] The screening method of the present application further comprises screening subjects suffering from an eye disease more frequently than healthy subjects. The method further includes determining, or having determined, one or more microbial species that are concentrated in the intraocular space of the subject. The eye diseases may be age-related macular degeneration (AMD), Behcet's disease (BD), cataracts ( Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH) ) and combinations thereof. For example, in some embodiments, the present invention provides a method for preparing a compound selected from: It is more concentrated in the intraocular space of subjects with age-related macular degeneration (AMD) than in healthy subjects. a) determining or having determined one or more microbial species present in the presence of a test compound; In a suitable medium, a microorganism containing at least one of the microbial species to be enriched is cultured. step b) measuring the growth of the microorganism in the medium in the presence of the test compound; and optionally, a candidate therapeutic agent that inhibits growth of said microorganism relative to a control. and d) determining whether the antibody is a soluble or soluble component of the antibody.

[0014] Some embodiments of the present invention relate to a method for producing the animal model of eye disease of the present application. The animal model is used for human eye diseases. The animal model produced by the above method is also included in the present invention. This is an embodiment.

[0015] Typically, methods for producing animal models involve the use of microorganisms and / or inactivated proteins derived from said microorganisms. The method includes introducing the microorganism into the intraocular space of the eye of an animal, wherein the microorganism is more likely to be present in a subject suffering from an ocular disease than in a healthy subject. The eye disease includes species that concentrate in the intraocular space of a subject suffering from cataracts (Cat), age-related macula glaucoma, AMD, glaucoma, Behçet's disease, Vogt, Koyanagi, and Harada The treatment is selected from the group consisting of ophthalmitis (VKH), endophthalmitis (EOS), and a combination thereof. induces one or more symptoms of the disease.

[0016] In some specific embodiments, the present invention provides methods for producing animal models of AMD. In some embodiments, the method comprises: the microorganism is more likely to cause AMD than a healthy subject. The introduction of the compound comprises a species that concentrates in the intraocular space of an affected subject, the species being capable of alleviating one or more symptoms of AMD. The method typically involves introducing live microorganisms into the intraocular space of an animal. In the present invention, the microorganisms to be introduced include at least live Bacillus megaterium. Alternatively, the animal is a non-human primate (e.g., a monkey). The object is a rhesus monkey.

[0017] The AMD animal model generated herein 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 method for detecting test compounds. a) administering to an AMD animal model as described above, and after administration, administering to one or more ocular diseases. b) determining the severity of symptoms, and optionally, and c) identifying a candidate therapeutic agent that ameliorates at least one of the Provide the law.

[0018] In some embodiments, the present invention also provides a method for treating or preventing the eye diseases of the present application, such as AMD. In some embodiments, the method provides a method for preventing Regarding the corresponding eye disease, such as AMD, identified by any of the screening methods of the present application, The method includes administering an effective amount of any candidate therapeutic agent to a patient.

[0019] In some embodiments, the present disclosure provides a method for the detection of AMD-associated microorganisms, such as Bacillus megateri. A compound containing a plurality of compounds capable of killing or inhibiting the growth of bacteria and / or bacteria. In some embodiments, the present disclosure relates to compositions comprising: Compounds according to any one of formulas I, III, IV-1, IV-2, and V and any of their subformulas In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt or ester thereof. The compound shown is any one of Compounds 1 to 8, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the compounds of the present disclosure may be derived from synthetic sources. In some embodiments, the compounds of the present disclosure are isolated or substantially pure compounds. It can also be an object.

[0020] In certain embodiments, one or more compounds of the present disclosure and any pharmaceutically acceptable excipients are For example, in some embodiments, the pharmaceutical composition comprises a compound represented by Formula I, II, or III. , III, IV-1, IV-2, V, a compound of any of these sub-formulas, or compounds 1 to 8 or a pharmaceutically acceptable salt or ester thereof, for example, in an amount of, for example, For example, the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, e.g., intestine, may be affected by the microorganisms of the present invention. Effective in killing or inhibiting the growth of organisms such as Bacillus megaterium The pharmaceutical compositions of the present application can be administered by any known route of delivery, such as oral, topical, intravitreal, intramuscular, or intravenous. In some embodiments, the composition may be formulated for delivery via intravenous, subcutaneous, or intravenous administration. The pharmaceutical compositions of the present application may, for example, contain an antibiotic and / or anti-VEGF agent as described herein. It may further comprise a GF drug.

[0021] In embodiments, the present disclosure provides a method for treating a patient suffering from a disease characterized by the use of a compound of the present disclosure or a pharmaceutical composition of the present disclosure. Treating microbial, e.g., Bacillus megaterium, infections (e.g., eye infections, e.g., in the intraocular space) and methods for treating or preventing diseases or disorders (e.g., AMD) associated with such infections. Further providing the law.

[0022] In some embodiments, the present disclosure provides a method for administering to a subject in need thereof a microorganism, such as a microbial For example, methods for killing or inhibiting the growth of Bacillus megaterium are provided. In some embodiments, the method includes administering to a subject a compound of the present disclosure (e.g., Formula I, II, III, IV-1 , IV-2, V, a compound of any of these subformulas, or any of compounds 1 to 8, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application) to a subject in a therapeutically effective amount. In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. The subject is at risk for developing AMD. In some embodiments, the subject's eye is In some embodiments, the method further comprises: Identify a person as having a microorganism, e.g., Bacillus megaterium, in the intraocular space. In some embodiments, the method further comprises, for example, identifying a Thus, the subject is further administered an antibiotic and / or an anti-VEGF drug.

[0023] In some embodiments, the present disclosure provides a method for treating or preventing AMD in a subject in need thereof. In some embodiments, the method comprises: , III, IV-1, IV-2, V, a compound of any of these sub-formulas, or compounds 1 to 8 or a pharmaceutically acceptable salt or ester thereof) in a therapeutically effective amount to a subject. In some embodiments, the method comprises the step of: and further comprising administering to the subject an antibiotic and / or an anti-VEGF drug. In this embodiment, AMD is characterized by drusen manifestations (hard drusen, soft drusen, mixed drusen, Dry or wet age-related macular degeneration with drusen and / or degenerated drusen, e.g. It may be dry or wet age-related macular degeneration with soft drusen symptoms. In embodiments, the method includes administering to a subject, for example, intraocularly, a microorganism of the present application, e.g., Bacillus megaterium, into the intraocular space. The method further includes the step of identifying or having identified the bacteria as infected. In embodiments, a subject may administer a microorganism of the present application, such as Bacillus megaterium, to, for example, the intraocular space. Infected.

[0024] In some embodiments, the present disclosure provides a method for the treatment of rheumatoid arthritis using Traditional Chinese Medicine (TCM) extracts with antibacterial activity. In some embodiments, the method provides a method for treating a pulmonary embolism in a subject in need thereof. Kills or inhibits the growth of the microorganism of the present application, and to treat an ocular infection (e.g., an eye infection, e.g., in the intraocular space) or to treat or prevent AMD. In some embodiments, the method comprises administering to a subject licorice (e.g., Glycyrrhiza uralensis), Chinese laurel (e.g., Cyn anchum otophyllum), forsythia (e.g., Forsythia s uspense), Citrus aurantium L., Geo Cormorant (e.g., Rehmannia glutinosa Libosch), Chinpi (e.g., Citrus reticulata Blanco), and Sancichi (e.g., Extracts derived from one or more TCMs selected from In some embodiments, the method includes administering to the subject, for example, intraocular Identifying or identifying the subject microorganism, e.g., Bacillus megaterium, as infecting the subject microorganism In some embodiments, the subject may further administer the method of the present application into the intraocular space, for example. The extract is a single TCM extract containing a microorganism, such as Bacillus megaterium. Or it may be an extract of one or more TCMs. Usually, the extract is an aqueous extract. In some embodiments, the extract is present in a liquid, semi-solid, or solid form, or any other form. In some embodiments, for example, as described herein, the subject may be administered an antibiotic A steroid and / or anti-VEGF drug is further administered.

[0025] In some embodiments, the present disclosure provides a method for treating a subject in need thereof with an antibiotic. and killing or inhibiting the growth of the microorganisms of the present invention, e.g., bacillus Treating S. megaterium infections (e.g., eye infections, e.g., in the intraocular space) or AMD In some embodiments, the methods are provided for treating or preventing, for example, As described, the method includes administering to the subject an effective amount of an antibiotic. In this condition, any commercially available antibiotic, e.g., a U.S. FDA-approved antibiotic, may be used. In some embodiments, the method includes providing a subject with a The microorganism of interest, e.g., Bacillus megaterium, is identified as infecting the target organism or the identified strain. In some embodiments, the subject may further administer the microorganisms of the present application, for example, into the intraocular space. In some embodiments, the subject is infected with, for example, Bacillus megaterium. As described in the application, the subject is further administered an anti-VEGF drug.

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

[0027] It should be noted that the above summary and the following detailed description are merely examples and interpretations, and the present invention This does not limit the scope of the present invention. [Brief explanation of the drawings]

[0028] [Figure 1] Figure 1 illustrates the susceptibility of Bacillus megaterium to multiple antimicrobial agents. [Figure 2] Illustrated is a culture in liquid cooked meat medium that is covered with liquid paraffin. [Figure 3]Detection of bacteria in cultures under standard light microscopy is shown. Observe the cultured E. coli under a light microscope. The negative control consists of sample preparation buffer inoculated with either AH or VH. Observe the bacteria in the cultured AH or VH samples (culture positive and negative samples) under a light microscope. [Figure 4] Photographs of the ocular surface and fundus of a rhesus monkey before and after inoculation with bacteria (Propionibacterium acnes (P. acnes) and Bacillus megaterium) are shown. The right eye (OD) and left eye (OS) of a rhesus monkey were inoculated with Propionibacterium acnes and Bacillus megaterium, respectively. Photographs of the ocular surface and fundus are shown before bacterial inoculation and 3 days after inoculation. [Figure 5] Photographs of the ocular surface and fundus of a rhesus monkey before and after inoculation with bacteria (Propionibacterium acnes and Pseudomonas putida) are shown. Propionibacterium acnes and Pseudomonas putida were inoculated into the right eye (OD) and left eye (OS), respectively. Photographs of the ocular surface and fundus are shown before and 3 days after inoculation. [Figure 6] Illustrates the anatomy and retinal location of subretinal injections. [Figure 7] This shows a fundus view of a rhesus macaque 47 days after injection, which received a subretinal inoculation of 20 CFU of AH culture, VH culture, and Bacillus megaterium. [Figure 8] 1 illustrates that antibiotic treatment can alter bacteria-induced drusenoid lesions in monkey retinal tissue. [Figure 9] Highly enriched species in the metagenomes of cataract, AMD, glaucoma, BD, and VKH patients' eyes, as identified using LefSe, are illustrated. [Figure 10] Each of compounds 1 to 8 effectively controls the growth of Bacillus megaterium. Test conditions: 1 mg of compound, Bacillus megaterium, concentration of 1 x 105 cells / 100 μl in 15 ml of medium. DETAILED DESCRIPTION OF THE INVENTION

[0029] In embodiments, the present disclosure is based in part on the fact that the environment within the eye is not sterile, and that some eyes This is based on the unexpected discovery that the endothelial microbiota can be a causative factor in several eye diseases, including AMD. The application, titled "METHODS AND COMPOSITIONS F" submitted on October 26, 2018, OR ASSESSING AND TREATING INTRAOCULAR DISEASES AND DISORDERS" PCT application no. No. PCT / CN2018 / 112022 (the contents of which are incorporated by reference in their entirety). These initial discoveries, detailed in the paper "The Microorganisms of the Bacteria," also provide insight into the role of these microorganisms, e.g., When administered live, B. megaterium: We found that the complement system can be activated in vivo in rhesus monkeys to induce drusenoid lesions. Furthermore, for example, intravitreal administration of the antibiotic vancomycin Killing or inhibiting the growth of such microorganisms results in a reduction in the number of rhesus monkeys compared to controls. The size of drusenoid lesions in retinal tissue can be reduced. See Example 9. These data and results suggest that such microorganisms, e.g., Bacillus megaterium, Agents that can kill or inhibit the growth of erythrocytes are useful in treating age-related macular degeneration. It is proven that:

[0030] For example, as detailed in PCT application number PCT / CN2018 / 112022, Cataract (Cat) 41 cases, AMD 20 cases, glaucoma (GLA) 18 cases, Behcet's disease ( 9 cases of BD, 9 cases of Vogt-Koyanagi-Harada syndrome (VKH), and 8 cases of endophthalmitis (EOS). Metagenomic sequencing analysis was performed on aqueous humor (AH) samples from patients. In particular, the major intraocular human microbiomes of all patients in these six types were Regardless of the bacterial component, both the alpha diversity and evenness of the ocular microbial community were clearly different. Principal component analysis was performed on the composition of the ocular microbiota (all microbial species were used). As shown by PCA, it is effective among patients with cataracts, EOS, and some glaucoma. However, in patients with AMD, VKH, BD, and some glaucoma, The intraocular human microbiome shares some indistinguishable characteristics. As revealed by hierarchical cluster analysis of the abundance of functional microbial genes from genomes In this study, each order showed common characteristics of microbial function, while each disease group showed other There are outliers that can be classified into disease clusters. Individuals with prominent intraocular human microbiomes Regardless of the sex, characteristic bacterial species can be identified for each of the ocular disease groups tested. The results clearly show that the composition and function of the ocular microbiota may affect ocular diseases, e.g. For example, it can distinguish between AMD, cataract, glaucoma, BD, VKH and EOS.

[0031] Metagenomic analysis identified 14 bacterial species highly enriched in the AH of AMD patients. Propionibacterium acnes was identified as the most abundant pathogen in the AH of AMD patients. Although the microorganisms were highly pathogenic, among the 14 AMD-specific species, Bacillus licheniformis B. licheniformis, and B. megaterium The most enriched species in AMD AH specimens was tetracycline. Compared with non-drusen retinal tissue from six archival eye slides from AMD patients, Fourteen types of AMD-specific bacteria were detected in hard drusen tissue and soft drusen tissue. PCR analysis was performed to examine whether or not the bacteria could be isolated. As a result, only eight types of bacteria were detected. Among these, Propionibacterium acnes was the most abundant species, Bacillus megaterium is a species that concentrates in soft drusen. The relative abundance of acnes in hard drusen, soft drusen, and dry AMD lesion tissues corresponds to that in non-drusen, non-diseased retinal tissue. The relative abundance of Bacillus megaterium was approximately 18-fold higher in soft drusen than in situ drusen. However, this is not the case in AMD lesions. and the possible role of Bacillus megaterium in the pathogenesis of AMD will be revealed. .

[0032] Previous studies have shown that, in addition to many other proteins, drusen contain multiple types of They contain complement components and polysaccharides. Furthermore, drusen components activate inflammasomes, Therefore, the present inventors first investigated the effects of drupelets on the expression of IL-1β and IL-18. Bacillus megaterium, a component of Zen, induces activation of the complement system in vitro and improves acute necrotic leukemia. Enhanced secretion of IL-1β and IL-18 by ARPE19 cells The present inventors investigated whether it is possible to use Propionibacterium acnes as a pathogen. We found that R. megaterium significantly increased pyroptosis in RPE cells in a time-dependent manner. Activation of the complement system was demonstrated by producing an active form of the C5A protein. Both bacteria induced CFH protein secretion by ARPE19 cells, while In contrast, Bacillus megaterium induces CFH, whereas Propionibacterium aeruginosa induces CFH. This is more evident than in the case of Propionibacterium acnes, which is a result of pyroptosis. In vitro infection with Bacillus megaterium, but not B. difficile, inhibits activated IL-1 by RPE cells. These results clearly show that Bacillus meliloti induces the secretion of IL-18 and IL-1β. Infection with G. gallium can cause inflammation similar to that found in soft drusen. There is a gender.

[0033] Next, we tested whether Bacillus megaterium can induce inflammation in vivo. The non-human primate rhesus monkey (Macaca fascicularis) laris) took into account the anatomical structure and intraocular environment of the eye shared by humans and rhesus monkeys. It is considered a model system. Propionibacterium acnes, which lives in the eye, Infection with or inoculation with its ultrasound-inactivated protein induces significant intraocular inflammation. However, it is not a protein but rather Bacillus megaterium, which lives in the eye. Infection with Bacillus megaterium causes significant intraocular inflammation. Induced intraocular inflammation increased the expression of TNFA and IL6, but not IFNG and IL17A. Importantly, only live Bacillus megaterium expresses C5A and CFH. Activation of the complement system, including the pyroptotic cytokines IL-1β and IL- 18. After the onset of inflammation, bacteria continue to survive in the eye, which These data suggest that intraocular inflammation can persist for a substantial period of time. Bacillus megaterium infection induces prolonged activation of the complement system in vitro and in vivo. , demonstrating that it can induce pyroptosis in eye cells.

[0034] Without wishing to be bound by theory, it is believed that bacteria such as Bacillus megaterium The fact that the RPE and brain are located in the nucleus and activate local complement-mediated immune responses is This explains the formation of various drusen between the membrane and the pericardium. All essential proteins (including complement components such as C1Q and immunoglobulins) are first-line antibodies. Other drusen proteins, such as vitronectin and apolipoprotein E, , which has recently been shown to be an anti-infective agent. Therefore, the formation of drusen is associated with aging. This is likely an important response in the control of invading bacterial pathogens in the retina. Due to the diversity of bacteria, the shape and size of drusen can vary. Once the infection is cleared, the drusen disappear. However, some pathogens, such as Bacillus S. megaterium induces long-term activation of immune responses in soft drusen and RPE It causes damage to cells and photoreceptors, and activates macrophages and RPE cells. Inflammation is a protective response against local infection, which is mediated by NLRP3. Activation of the inflammasome and production of IL-18 prevent retinal neovascularization. This is consistent with previous findings.

[0035] Without wishing to be bound by theory, all genetic studies, including the infectious etiology of AMD, For example, defective CFH (induced by Bacillus megaterium infection) Defective HTRA1 (a negative regulator of complement activation) leads to uncontrolled complement activation. A protease that produces the active form of the immunosuppressive cytokine TGF-β is a local TGF- These two genetic mutations result in a decrease in RPE cells and β family proteins. It causes dysregulation of local anti-infective responses that impair photoreceptors.

[0036] Furthermore, potential differences in the pathogenic microbiota found in drusen may be related to different genetic risks. Associations between factors and different ethnicities (e.g., Caucasian and Asian) can be interpreted. Therefore, the infectious etiology of AMD is a mechanism that causes early AMD pathology in elderly people. There is evidence to suggest this.

[0037] In summary, in some embodiments, the inventors have demonstrated that a method for killing and / or inhibiting the growth of microorganisms is When inhibited, it can reduce AMD symptoms such as drusen symptoms (hard drusen, soft drusen, mixed drusen). Dry or wet age-related macular degeneration with drusen and / or degenerated drusen, e.g. The present invention relates to the treatment and / or prevention of dry or wet age-related macular degeneration with soft drusen symptoms. This will reveal the following.

[0038] Screening Method The discovery that multiple intraocular diseases are associated with specific microorganisms also contributes to the identification of intraocular diseases such as AMD. Thus, some embodiments of the present invention support methods for screening candidate therapeutic agents. The embodiments relate to a number of screening methods. The screening methods of the present application include in vitro In vivo methods (e.g., in culture dishes) or in vivo methods (e.g., using the animal models described herein) ) may also be used.

[0039] In some embodiments, the present invention provides a screening method, 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 and c) identifying candidate therapeutic agents that inhibit the growth of the microorganism. The intraocular space (e.g., aqueous humor in the anterior chamber) of subjects with ocular diseases is larger than that of healthy subjects. , suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens or iris), and the eye disease is age-related macular degeneration (AMD), Behcet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), V OGT-Koyanagi-Harada syndrome (VKH) and combinations thereof. In embodiments, the method comprises: providing a method for determining whether a subject suffering from an ocular disease has a higher intraocular space than a healthy subject; The method further comprises a step d) of determining or having determined one or more microbial species to be enriched, The diseases include age-related macular degeneration (AMD), Behcet's disease (BD), cataracts (Cat), and endophthalmitis. (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations of these In this method, the healthy subjects used for comparison are selected from a group consisting of subjects without ocular diseases. The term "control" referred to in the method refers to a placebo control without the test compound. It will be obvious to one skilled in the art how to carry out appropriate experiments for comparison. In any of the foregoing embodiments of the present application, to the extent not directly contradictory, the subject may be a human subject. In any of the foregoing embodiments of the present application, to the extent not directly contradictory, the screening method may further comprise: by identifying candidate therapeutic agents for treating or preventing human diseases, such as the human ocular diseases of the present application; Applicable.

[0040] In some embodiments, the present invention provides a compound or combination of compounds for the treatment or prevention of eye diseases. The present invention provides a method for screening the efficacy of a combination of eye diseases, the method comprising: The subject, a family member or close genetic relative of the subject who is suffering from said eye disease, or a person who is suffering from said eye disease The aqueous humor or vitreous humor of a subject selected from deceased subjects known to have the disease obtaining a sample under conditions selected from conditions that mimic the intraocular space of a human eye; Alternatively, one or more organisms from the sample are cultured in a cooked meat medium, and one or more producing a culture and injecting the compound or combination of compounds into the one or more cultures. and said compound or combination of compounds is added to said one or more cultures. and determining whether the growth or population is reduced. and growing the one or more cultures in vitro based on the determined results. or the further step of identifying a compound or combination of compounds that reduces the population. That's fine.

[0041] In some embodiments, family members are members of the subject's immediate family, e.g., parents, children, or siblings. In some embodiments, the family may include a patient with a long-standing eye disease. In some embodiments, close genetic contacts may include people who occupy the same living space as the subject. The relationship may include the relationship of a subject suffering from the disease, which relationship may be related to the genetic makeup of the subject. Within three direct generations of the family relationship, for example, the subject's great-grandparents, grandparents, parents, children, grandchildren / In some embodiments, the close genetic relationship is a sibling of the subject. In some embodiments, a close genetic relationship may include a brother or sister who is affected by the disease. The subject may be related to a collateral relationship, such as a father-in-law or uncle of the subject. Includes sisters, cousins, nieces, and nephews.

[0042] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating or preventing an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidi 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 further comprises identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro based on the results of the determination.

[0043] In some embodiments, the present invention provides a compound or combination of compounds for the treatment or prevention of eye diseases. The present invention provides a method for screening the efficacy of a combination of eye diseases, the method comprising: The subject, a family member or close genetic relative of the subject who is suffering from said eye disease, or a person who is suffering from said eye disease The aqueous humor or vitreous humor of a subject selected from deceased subjects known to have the disease obtaining a sample under conditions selected from conditions that mimic the intraocular space of a human eye; Alternatively, one or more organisms from the sample are cultured in a cooked meat medium, and one or more Producing a culture and one or more inactivated proteins derived from said one or more cultures. obtaining a solution of said compound or combination of compounds and said one or more and mixing the compound or combination of compounds with the inactivated protein solution. and determining whether the one or more inactivating proteins bind to the one or more inactivating proteins.

[0044] In some embodiments, the present invention provides a compound or combination of compounds for the treatment of ocular diseases. The present invention provides a method for screening the efficacy of the method, the method comprising administering to a subject suffering from the eye disease, Family or close genetic relatives of the subject who suffers from said eye disease, or The aqueous humor or vitreous humor was collected from deceased subjects known to have obtaining a sample and performing the sample under conditions selected from conditions that mimic the human intraocular space or Cultivating one or more organisms from the sample in a cucumber medium, and culturing one or more cultures producing one or more inactivated proteins derived from said one or more cultures; and administering the one or more inactivated proteins to a mammalian inflammation model. and introducing said compound or combination of compounds into said mammalian inflammation model. and determining whether said compound or combination of compounds has inflammatory activity in said model. and determining whether to decrease the

[0045] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating or preventing an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebuleus, Acinetobacter bauma The method further comprises obtaining a solution of one or more inactivated proteins derived from the one or more cultures of a strain selected from the group consisting of Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, Finegoldia magna, and combinations thereof, 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 further comprises identifying a compound or combination of compounds that binds the one or more inactivated proteins in vitro based on the results of the determination.

[0046] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating or preventing an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebuleus, Acinetobacter baumannii, Acinetobacter calciferol, The method includes obtaining a solution of one or more inactivated proteins derived from one or more cultures selected from the group consisting of Bacillus coaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, Finegoldia magna, and combinations thereof; 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 identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro based on the results of the determination. 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 compound or combination of compounds for the treatment or prevention of eye diseases. The present invention provides a method for screening the effectiveness of a compound or a combination of compounds. administering a combination of the compound or the combination of compounds to said mammalian model of the present application; determining whether the combination effectively reduces or prevents one or more symptoms of said eye disease. In some embodiments, the mammalian model includes a drusenoid pathology. Once formed, the compound or combination of compounds is administered. , a compound or a combination of compounds can be identified by the in vitro screening method of the present application. In some embodiments, one or more compounds or combinations of compounds are identified. The injection may include intraocular injection. In some embodiments, the one or more symptoms are ocular hyperplasia (ocular hyperplasia). The development of senoid lesions, microbial growth or load, production of inflammatory molecules or markers, and is selected from the group consisting of a combination of:

[0048] The microorganisms used in the method may be substantially biologically pure species or a plurality of different species. In some embodiments, the microorganism is at least one species that is a causative agent of an ocular disease. In some embodiments, the microorganism comprises at least one species, Killing or inhibiting the growth of at least one species is beneficial in treating or preventing eye diseases. Any technique known in the art may be used to culture the microorganisms and select the medium. Some exemplary details are provided in the Examples section. Alternatively, the microorganisms may be cultured in a liquid cooked meat medium. The growth of the microorganisms is measured or determined. The method is not particularly limited and is generally known in the art. In this application, the method is described in the Examples section. Several exemplary methods are described. For the avoidance of doubt, the present application refers to the use of a method for the growth of microorganisms. The measurement or determination does not require a quantitative measurement. The test compound prevents visible growth of the microorganism at or below the maximum test concentration and / or If the compound prevents the formation of visible colonies of microorganisms at or below the maximum test concentration, the compound is It is enough to just observe.

[0049] Candidate therapeutic agents may be identified by any suitable technique known in the art. In some embodiments, a test compound inhibits the growth of a microorganism relative to a control at concentrations up to the maximum test concentration. If so, they may be identified as candidate therapeutic agents for treating or preventing, for example, the corresponding eye disease. In some embodiments, the test compound prevents visible growth of the microorganism at or below the maximum test concentration. If the test compound inhibits the growth of the tumor, it may be identified as a candidate therapeutic agent. A potential therapeutic agent is one that prevents visible colony formation of the microorganism at or below the maximum test concentration. can be identified.

[0050] Test compounds 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. The concentrations allow comparisons between different test compounds and allow further identification of candidate therapeutic agents. This is advantageous for selection / determination.

[0051] Screening Methods for AMD In some particular embodiments, the screening method can be used to identify candidate therapeutic agents for treating or preventing AMD. In any of the above embodiments of the present application, unless the context clearly indicates otherwise, AMD can be dry or wet age-related macular degeneration with drusen symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), e.g., dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method includes steps a) culturing microorganisms in an appropriate 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. Typically, the microorganisms include 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 humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of subjects with AMD than in healthy subjects. For example, in some embodiments, the microorganisms include species that are enriched in the aqueous humor, vitreous humor, and / or soft drusen of subjects with AMD compared to healthy controls. 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 faecali ... Faecium In some embodiments, the microorganism may comprise one or more species selected from Bacillus megaterium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the microorganism may comprise Bacillus megaterium and / or Pseudomonas putida. In some embodiments, the microorganism comprises at least Bacillus megaterium. In some embodiments, the microorganism may be a substantially biologically pure population of Bacillus megaterium.

[0052] Various initial concentrations of microorganisms can be used in the screening method of the present application. In some embodiments, for the screening methods of the present application, about 10 μL (microliters) 100µL) to about 500µL (e.g., about 100µL) with a concentration of about 1*10 5 ~1*10 9 ( For example, about 1*10 6 , about 1*10 8 Or about 1*10 8 ) cells / mL of Bacillus megaterium The suspension is placed in a culture dish containing approximately 10 to 15 mL of medium, and incubated at an appropriate temperature and conditions, e.g. Incubation may be performed at 37° C. for 24 hours. For example, in some embodiments, Regarding the screening method, approximately 1*10 5 ~1*10 9 (e.g., about 1*10 5 or 1*10 7 ) Bacillus megaterium may be used.

[0053] In some embodiments, the microorganism may comprise a mixture of microbial species, said microbial species comprising: Observed in aqueous humor, vitreous humor, and / or soft drusen in subjects with age-related macular degeneration For example, in some embodiments, the method is substantially similar to that described above. Pathogenic species identified in the aqueous humor, vitreous humor, and / or soft drusen of subjects with The term "substantially similar" means that the microorganism is similar to the A Microscopic findings in the aqueous humor, vitreous humor, and / or soft drusen of subjects with MD It is not required that the organisms have the same microbial species composition as the biological species. , concentrated in the aqueous humor, vitreous humor and / or soft drusen of subjects suffering from AMD ( It is sufficient to include a (preferably pathogenic) microbial species, for example as described herein. The term "substantially similar" when used in conjunction with other eye diseases should be understood similarly. In some embodiments, the microorganism is present in a subject who is partially or completely affected by age-related macular degeneration. For example, in some embodiments, the aqueous humor and / or vitreous humor may be derived from In this study, microorganisms were isolated from the aqueous humor and / or vitreous humor of subjects suffering from age-related macular degeneration. In some embodiments, the test compound may be added to a sample. If the substance inhibits the growth of a microorganism (e.g., Bacillus megaterium) compared to a control, The compounds may be identified as candidate therapeutic agents for treating or preventing AMD.

[0054] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing AMD is provided. The training method was more effective in subjects with age-related macular degeneration (AMD) than in healthy subjects. Step a) determining or having determined one or more microbial species that are concentrated in the intraocular space; and testing In the presence of the compound, a microbial culture containing at least one of the microbial species to be enriched is grown in a suitable medium. b) culturing the microorganism in the medium in the presence of the test compound; and optionally, inhibiting growth of said microorganism relative to a control. and d) identifying a candidate therapeutic agent.

[0055] In some embodiments, the determination is more likely to occur in subjects with AMD than in healthy subjects. The objective of the present invention may be to obtain information on the concentration of one or more microbial species in the intraocular space of the subject. In some embodiments, the determining is performed by measuring intraocular space of a subject suffering from AMD. assessing the presence, absence and / or amount of microorganisms in a sample of The presence, absence and / or amount of the microorganism may be compared with a healthy control. The method for assessing the presence, absence and / or amount of a substance is described in PCT Application No. PCT / CN2018 / 1 12022. In some embodiments, the microorganism is a mixture of microbial species. The microbial species may be present in the aqueous humor, vitreous humor, or the like of a subject suffering from age-related macular degeneration. and / or substantially similar to that observed in soft drusen. In this embodiment, the microorganisms are present in the aqueous humor and / or retinal fluid of a subject who is partially or completely affected by age-related macular degeneration. For example, in some embodiments, the microorganisms may be derived from the vitreous humor. A sample obtained from the aqueous humor and / or vitreous humor of a subject suffering from age-related macular degeneration. In some embodiments, the test compound may be used as a control. If the compound inhibits the growth of microorganisms compared to the compound, it is a candidate therapeutic agent for treating or preventing AMD. can be identified as such.

[0056] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing AMD is provided. The scanning method involves collecting a sample from the intraocular space of a subject suffering from AMD, e.g., aqueous humor, a) obtaining vitreous humor and / or soft drusen; b) culturing the vitreous humor and / or soft drusen in the presence of a test compound; b) incubating the sample in the presence of the test compound; c) measuring the growth of the microorganism in said medium, and optionally comparing said growth rate to a control. and d) identifying candidate therapeutic agents that inhibit the growth of the microorganism. 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 humor of a subject suffering from AMD. In some embodiments, the sample is soft drupe material from a subject suffering from AMD. As shown in the Examples section of this application, the incubation of the samples is To avoid contamination with microbial species not present in the subject's sample in the first place, the sample is usually prepared in a sterile environment (e.g., In some embodiments, a negative control is used. In some embodiments, the test compound may inhibit the growth of microorganisms in the culture medium compared to a control. If it inhibits growth, it may be identified as a candidate therapeutic agent for treating or preventing AMD.

[0057] In some embodiments, the present invention provides a compound or compounds for the treatment or prevention of AMD. The present invention provides a method for screening the efficacy of a combination of AMD, the method comprising: The subject, family members or close genetic relatives of the subject who have AMD, or anyone who has AMD The aqueous humor or vitreous humor of a subject selected from deceased subjects known to be and obtaining a sample selected from conditions simulating the human intraocular space. Cultivating one or more organisms from the sample under conditions or in cooked meat medium, producing one or more cultures of the compound or combination of compounds; and adding the compound or combination of compounds to the culture medium. and determining whether the growth or population of the culture is reduced. In embodiments, the method further comprises culturing the one or more species in vitro based on the determination. identifying a compound or combination of compounds that reduces growth or population of the organism; It may further include:

[0058] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidi 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 further comprises identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro based on the results of the determination.

[0059] In some embodiments, the present invention provides a compound or compounds for the treatment or prevention of AMD. The present invention provides a method for screening the efficacy of a combination of AMD, the method comprising: The subject, family members or close genetic relatives of the subject who have AMD, or anyone who has AMD The aqueous humor or vitreous humor of a subject selected from deceased subjects known to be and obtaining a sample containing the sample under conditions simulating the human intraocular space or cooked meat. Cultivating one or more organisms from the sample in a medium to produce one or more cultures. and a solution of one or more inactivated proteins derived from said one or more cultures. and obtaining said compound or combination of compounds and said one or more inactivated proteins. and mixing the compound or combination of compounds with a solution of the compound. and determining whether the inactivating protein binds to the inactivating protein.

[0060] In some embodiments, the present invention provides a compound or compounds for the treatment or prevention of AMD. The present invention provides a method for screening the efficacy of a combination of AMD, the method comprising: The subject, family members or close genetic relatives of the subject who have AMD, or anyone who has AMD The aqueous humor or vitreous humor of a subject selected from deceased subjects known to be obtaining a sample containing the sample; and performing the sample under conditions selected from conditions that mimic the intraocular space of a human eye or Cultivating one or more organisms from the sample in a cooked meat medium, and and producing one or more inactivated proteins derived from said one or more cultures. obtaining a protein solution; and administering the one or more inactivated proteins to a mammalian inflammation model. and administering the compound or combination of compounds to the mammalian inflammation model. and determining whether said compound or combination of compounds has an inflammatory activity in said model. and determining whether to reduce the sensitivity.

[0061] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating or preventing an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebuleus, Acinetobacter bauma The method further comprises the steps of: obtaining a solution of one or more inactivated proteins derived from the one or more cultures of a strain selected from the group consisting of Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, Finegoldia magna, and combinations thereof; 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 vitro. In some embodiments, the method further comprises identifying a compound or combination of compounds that binds the one or more inactivated proteins in vitro based on the results of the determination.

[0062] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds for treating an ocular disease, the method comprising culturing one or more organisms under conditions selected from conditions that mimic the human intraocular space or in a cooked meat medium to produce one or more cultures, wherein the one or more organisms are selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythrorhizus ... Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebuleus, Acinetobacter baumannii, Acinetobacter calciferol, The method includes obtaining a solution of one or more inactivated proteins derived from one or more cultures selected from the group consisting of Bacillus coaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, Finegoldia magna, and combinations thereof; 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 identifying a compound or combination of compounds that reduces the growth or population of the one or more cultures in vitro based on the results of the determination. 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 compound or combination of compounds for the treatment of ocular diseases. The present invention provides a method for screening the effectiveness of a compound or combination of compounds, the method comprising: administering to said mammalian model a compound or combination of compounds of the present application; and determining whether the treatment effectively reduces or prevents one or more symptoms of AMD. In some embodiments, after formation of drusenoid lesions in the mammalian model, In some embodiments, the compound or combination of compounds is administered. The combination of compounds identified by the in vitro screening method of the present application In some embodiments, administration is by intraocular injection. In some embodiments, the one or more symptoms may include drusenoid lesions. development of inflammatory molecules or markers, microbial growth or load, and combinations thereof is selected from the group consisting of:

[0064] Screening methods for other diseases In some embodiments, the screening method comprises screening for candidate therapeutic agents for treating or preventing BD. In some embodiments, the method can be used to identify an appropriate a) culturing a microorganism in a medium; and b) culturing the microorganism in the medium in the presence of the test compound. and b) measuring the growth of the microorganisms in the BD-affected subjects more than in healthy subjects. The affected subject's intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, and ciliary muscle) This includes species that concentrate in the vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris. For example, in some embodiments, the microorganisms are detected in subjects with BD compared to healthy controls. In some embodiments, the microorganisms include species that concentrate in the aqueous humor and / or vitreous humor of a subject. Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fluorescens ssens, Ralstonia picketii, Lactobacillus crispatus, Burkholderi A. multivorans, Lactobacillus delbrueckii, and Meiothermus sylvanus In some embodiments, the microorganism may include one or more species selected from (D). The microbial species may comprise a mixture of biological species, the microbial species being present in the aqueous humor and the aqueous humor of a subject suffering from BD. and / or substantially similar to that observed in the vitreous humor. The organisms originate in the aqueous humor and / or vitreous humor of a subject suffering in part or in whole from BD. For example, in some embodiments, the microorganism may be a microorganism that is associated with BD. Obtained by culturing samples obtained from the subject's aqueous humor and / or vitreous humor. In some embodiments, the test compound inhibits the growth of the microorganism relative to a control. If so, the compound may be identified as a candidate therapeutic agent for treating or preventing BD.

[0065] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing BD is provided. The screening method is to identify a type of ophthalmologist that is more concentrated in the intraocular space of subjects with BD than in healthy subjects. Step a) is to determine or have determined the above microbial species, and in the presence of a test compound, Step b. Cultivating microorganisms containing at least one of the microbial species to be enriched in a medium. ) and step c) measuring the growth of the microorganism in the medium in the presence of the test compound. and optionally, a sequence for identifying candidate therapeutic agents that inhibit growth of said microorganism relative to a control. In some embodiments, the determining may further comprise step d). Rather than the usual microbial species, the intraocular space of subjects with BD is enriched with one or more microbial species. In some embodiments, the determination may involve obtaining information about whether the patient is suffering from BD. The presence, absence and / or quantity of microorganisms in samples from the intraocular space of affected subjects and optionally comparing the presence, absence and / or amount of said microorganism with that of a healthy control. The method for assessing the presence, absence and / or amount of a microorganism may be as set forth in PCT Application No. In some embodiments, the present invention includes those described in PCT / CN2018 / 112022. The microorganisms may comprise a mixture of microbial species, said microbial species being present in a subject suffering from BD. Substantially similar to that observed in the aqueous humor and / or vitreous humor. In this study, microorganisms were detected in the aqueous and / or vitreous humor of subjects who were partially or completely affected by BD. For example, in some embodiments, the microorganism may be derived from a pathogenic bacterium (BD)-associated bacterium. by culturing samples obtained from the aqueous humor and / or vitreous humor of subjects In some embodiments, the test compound inhibits the growth of the microorganism as compared to a control. If the compound inhibits BD, it may be identified as a candidate therapeutic agent for treating or preventing BD.

[0066] In some embodiments, a screening method for identifying candidate therapeutic agents for treating or preventing BD is provided. The screening method involves collecting a sample from the intraocular space of a subject suffering from BD, e.g., aqueous humor and / or a) obtaining vitreous humor; b) incubating said sample in a medium in the presence of a test compound; b) incubating and growing the microorganism in the medium in the presence of the test compound. and optionally, inhibiting growth of said microorganism relative to a control. and d) identifying a candidate therapeutic agent. The sample is obtained from the aqueous humor of a subject suffering from BD. The sample is obtained from the vitreous humor of a subject suffering from BD. As shown in Figure 1, the sample incubation time is 10 minutes, and the sample incubation time is 10 minutes. To avoid contamination with microbial species, the samples are usually prepared in a sterile medium in a sterile environment (e.g., a sealed environment). In some embodiments, a negative control may be used. If the test compound inhibits the growth of the microorganism in the medium compared to the control, the BD is treated. or may be identified as a candidate therapeutic agent for preventing or treating the disease.

[0067] In some embodiments, the screening method comprises screening for a candidate therapeutic agent that treats or prevents cataracts. In some embodiments, the method can be used to identify appropriate a) culturing a microorganism in a suitable medium; and b) culturing the microorganism in the medium in the presence of the test compound. and b) measuring the growth of the organism, wherein the microorganism is more likely to cause cataracts than healthy subjects. The intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary plexus, Contains species that concentrate in the retina, choroid, optic nerve, lens, or iris (vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris) For example, in some embodiments, the microorganisms are present in individuals with cataracts compared to healthy controls. In some embodiments, the microorganisms include species that concentrate in the aqueous humor and / or vitreous humor of a subject. The organisms are Pseudomonas mendocina, Chitococcus sedentarius, and Alicycliphilus. Sphingobium denitrificans, Achromobacter xyloxidans, Sphingobium sphingobium japonicum, Mycobacterium abscessus, Arthrobacter aurescens, Pre Botela dentalis, Sinorhizobium meliloti, and Acidovorax ebuleu In some embodiments, the microorganism may comprise one or more species selected from the group consisting of microorganisms. The microbial species may comprise a mixture of species, the microbial species being present in the aqueous humor and / or aqueous humor of a subject suffering from a cataract. or substantially similar to that observed in the vitreous humor. The substance is derived from aqueous humor and / or vitreous humor of a subject who is partially or completely affected by cataracts. For example, in some embodiments, the microorganism may be a microorganism that is afflicted with cataracts. by culturing samples obtained from the aqueous humor and / or vitreous humor of a subject In some embodiments, the test compound inhibits the growth of the microorganism relative to a control. If so, they may be identified as candidate therapeutic agents for treating or preventing cataracts.

[0068] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing cataracts is provided. The scanning method is more concentrated in the intraocular space of subjects with cataracts than in healthy subjects. a) determining or having determined one or more microbial species; and b) determining the presence of a test compound, as appropriate. A step of culturing microorganisms containing at least one of the microbial species to be enriched in an appropriate medium. b) measuring the growth of the microorganism in the medium in the presence of the test compound. c) and, optionally, identifying candidate therapeutic agents that inhibit growth of said microorganism relative to a control. In some embodiments, the determination may further include a step (d) of determining whether a healthy subject has a high risk of developing a heart attack or a stroke. One or more microbial species are more concentrated in the intraocular space of subjects with cataracts than those without. In some embodiments, the determination may involve obtaining information about Presence, absence and / or quality of microorganisms in samples from the intraocular space of subjects suffering from a disorder or amount, and optionally comparing the presence, absence and / or amount of said microorganism with a healthy control. The method for assessing the presence, absence and / or amount of a microorganism may be a PCT Some embodiments include those described in application number PCT / CN2018 / 112022. In the present invention, the microorganisms may comprise a mixture of microbial species, and the microbial species may be selected from the group consisting of microbial species that are associated with cataracts. The results are substantially similar to those observed in the aqueous and / or vitreous humor of some subjects. In this embodiment, the microorganisms are present in the aqueous humor and / or the aqueous humor of a subject partially or completely suffering from a cataract. For example, in some embodiments, the microorganisms may be derived from the vitreous humor. , culturing a sample obtained from the aqueous humor and / or vitreous humor of a subject suffering from a cataract. In some embodiments, the test compound may be , which inhibits the growth of microorganisms, are identified as candidate therapeutic agents for treating or preventing cataracts. It can be done.

[0069] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing cataracts is provided. The scanning method involves collecting samples from the intraocular space of a subject suffering from a cataract, such as aqueous humor and a) obtaining the sample and / or vitreous humor in a medium in the presence of a test compound; b) incubating the culture medium with the microorganisms in the presence of the test compound; and optionally, measuring the growth of said microorganisms relative to a control. and d) identifying a candidate therapeutic agent that inhibits the growth of the tumor. In the present study, a sample is obtained from the aqueous humor of a subject suffering from a cataract. In one embodiment, the sample is obtained from the vitreous humor of a subject suffering from cataracts. As shown in the Examples section, sample incubation is performed by first incubating the sample from the subject. To avoid contamination with non-existent microbial species, the process is usually carried out in a sterile environment (e.g., a closed environment). In some embodiments, a negative control may be used. In embodiments of the present invention, a test compound is detected when it inhibits growth of the microorganism in the culture medium relative to a control. They may be identified as candidate therapeutic agents for treating or preventing cataracts.

[0070] In some embodiments, the screening method comprises screening for a candidate therapeutic agent for treating or preventing GLA. In some embodiments, the method can be used to identify appropriate a) culturing a microorganism in a suitable medium; and b) culturing the microorganism in the medium in the presence of the test compound. and b) measuring the growth of the organism, wherein the organism has a higher GLA content than the healthy subject. The intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary plexus, Contains species that concentrate in the retina, choroid, optic nerve, lens, or iris (vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris) For example, in some embodiments, the microorganisms are affected by GLA compared to healthy controls. In some embodiments, the microorganisms include species that concentrate in the aqueous humor and / or vitreous humor of a subject. The bacteria are Acinetobacter baumannii, Acinetobacter calcoaceticus, and Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Trobacter koseri, Diadobacter fermentans, and Serratia marcescens In some embodiments, the microorganism may comprise one or more species selected from the group consisting of: The microbial species may comprise a mixture of biological species, the microbial species being present in the aqueous humor and the aqueous humor of a subject suffering from GLA. In some embodiments, the vitreous humor is substantially similar to that observed in the vitreous humor. The microorganisms originate in the aqueous and / or vitreous humor of subjects partially or completely affected by GLA. For example, in some embodiments, the microorganism may be a GLA-infected microorganism. by culturing samples obtained from the aqueous humor and / or vitreous humor of subjects In some embodiments, the test compound inhibits the growth of the microorganism compared to a control. If so, it may be identified as a candidate therapeutic agent for treating or preventing GLA.

[0071] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing GLA is provided. The scanning method is more concentrated in the intraocular space of subjects with GLA than in healthy subjects. a) determining or having determined one or more microbial species; and b) determining the presence of a test compound, as appropriate. A step of culturing microorganisms containing at least one of the microbial species to be enriched in an appropriate medium. b) measuring the growth of the microorganism in the medium in the presence of the test compound. c) and, optionally, identifying candidate therapeutic agents that inhibit growth of said microorganism relative to a control. In some embodiments, the determining may further comprise step d) determining whether the patient is a healthy subject. One or more microbial species are more concentrated in the intraocular space of subjects with GLA than in examiners. In some embodiments, the determination may involve obtaining information about G The presence, absence and severity of microorganisms in samples from the intraocular space of subjects with LA and / or amount of said microorganism, and optionally comparing the presence, absence and / or amount of said microorganism with that of a healthy control. The method for assessing the presence, absence and / or amount of microorganisms may be a comparison with PC Some embodiments are described in PCT Application No. PCT / CN2018 / 112022. In some embodiments, the microorganism may comprise a mixture of microbial species, said microbial species being affected by GLA. The results are substantially similar to those observed in the aqueous and / or vitreous humor of subjects with In some embodiments, the microorganisms are present in the aqueous humor and / or the aqueous humor of a subject partially or completely affected by GLA. For example, in some embodiments, microorganisms may be present in the vitreous humor. The present invention relates to the culture of samples obtained from aqueous humor and / or vitreous humor of subjects suffering from GLA. In some embodiments, the test compound may be administered to a subject in a manner similar to that of a control. If the compound inhibits the growth of microorganisms, it is considered a candidate therapeutic agent for treating or preventing GLA. It can be determined.

[0072] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing GLA is provided. The scanning method involves collecting samples from the intraocular space of a subject suffering from GLA, e.g., aqueous humor and a) obtaining the sample and / or vitreous humor in a medium in the presence of a test compound; b) incubating the culture medium with the microorganisms in the presence of the test compound; and optionally, measuring the growth of said microorganisms relative to a control. and d) identifying a candidate therapeutic agent that inhibits the growth of the tumor. In this study, a sample is obtained from the aqueous humor of a subject suffering from GLA. In one embodiment, the sample is obtained from the vitreous humor of a subject suffering from GLA. As shown in the Examples section, sample incubation is performed by first incubating the sample from the subject. To avoid contamination with non-existent microbial species, the process is usually carried out in a sterile environment (e.g., a closed environment). In some embodiments, a negative control may be used. In embodiments of the present invention, a test compound is detected when it inhibits growth of the microorganism in the culture medium relative to a control. GLA may be identified as a candidate therapeutic agent for treating or preventing GLA.

[0073] In some embodiments, the screening method comprises screening for a candidate therapeutic agent for treating or preventing VKH. In some embodiments, the method can be used to identify appropriate a) culturing a microorganism in a suitable medium; and b) culturing the microorganism in the medium in the presence of the test compound. and b) measuring the growth of the organism, wherein the microorganism is more likely to be VKH than in healthy subjects. The intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary plexus, Contains species that concentrate in the retina, choroid, optic nerve, lens, or iris (vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris) For example, in some embodiments, the microorganisms are more susceptible to VKH than healthy controls. In some embodiments, the microorganisms include species that concentrate in the aqueous humor and / or vitreous humor of a subject. The bacteria are Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurumcoccus Some implementations include one or more species selected from the group consisting of: In some embodiments, the microorganisms may comprise a mixture of microbial species, said microbial species being those affected by VKH. The results are substantially similar to those observed in the aqueous and / or vitreous humor of subjects. In some embodiments, the microorganisms are present in the aqueous humor and the aqueous humor of a subject partially or completely affected by VKH. For example, in some embodiments, the microbial The subject is a subject with VKH, and the subject is a subject with VKH. The subject is a subject with VKH. In some embodiments, the test compound may be cultured to obtain a If all of these compounds inhibit the growth of microorganisms, they are considered candidate therapeutic agents for treating or preventing VKH. can be identified.

[0074] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing VKH is provided. The scanning method is more concentrated in the intraocular space of subjects with VKH than in healthy subjects. a) determining or having determined one or more microbial species; and b) determining the presence of a test compound, as appropriate. A step of culturing microorganisms containing at least one of the microbial species to be enriched in an appropriate medium. b) measuring the growth of the microorganism in the medium in the presence of the test compound. c) and, optionally, identifying candidate therapeutic agents that inhibit growth of said microorganism relative to a control. In some embodiments, the determining may further comprise step d) determining whether the patient is a healthy subject. One or more microbial species are more concentrated in the intraocular space of subjects with VKH than in examiners. In some embodiments, the determination may involve obtaining information about V The presence, absence, and severity of microorganisms in samples from the intraocular space of subjects with KH and / or amount of said microorganism, and optionally comparing the presence, absence and / or amount of said microorganism with that of a healthy control. The method for assessing the presence, absence and / or amount of microorganisms may be a comparison with PC Some embodiments are described in PCT Application No. PCT / CN2018 / 112022. In some embodiments, the microorganism may comprise a mixture of microbial species, said microbial species being affected by VKH. The results are substantially similar to those observed in the aqueous and / or vitreous humor of subjects with In some embodiments, the microorganisms are present in the aqueous humor and / or the aqueous humor of a subject partially or completely affected by VKH. For example, in some embodiments, microorganisms may be present in the vitreous humor. The present study cultured samples obtained from aqueous humor and / or vitreous humor of subjects suffering from VKH. In some embodiments, the test compound may be administered to a subject in a manner similar to that of a control. If the compound inhibits the growth of the microorganism, it is considered a candidate therapeutic agent for treating or preventing VKH. It can be determined.

[0075] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing VKH is provided. The scanning method involves collecting samples from the intraocular space of a subject suffering from VKH, e.g., aqueous humor and a) obtaining the sample and / or vitreous humor in a medium in the presence of a test compound; b) incubating the culture medium with the microorganisms in the presence of the test compound; and optionally, measuring the growth of said microorganisms relative to a control. and d) identifying a candidate therapeutic agent that inhibits the growth of the tumor. In this study, a sample is obtained from the aqueous humor of a subject suffering from VKH. In one embodiment, the sample is obtained from the vitreous humor of a subject suffering from VKH. As shown in the Examples section, sample incubation is performed by first incubating the sample from the subject. To avoid contamination with non-existent microbial species, the process is usually carried out in a sterile environment (e.g., a closed environment). In some embodiments, a negative control may be used. In embodiments of the present invention, a test compound is detected when it inhibits growth of the microorganism in the culture medium relative to a control. VKH may be identified as a candidate therapeutic agent for treating or preventing VKH.

[0076] Test Compound Test compounds used in the screening methods of the present application (e.g., candidates for treating or preventing AMD) There is no particular limitation on the type of test compound (used to identify a therapeutic agent). a molecule, a biological product (including polypeptides and polynucleotides), or a combination of a small molecule and a biological product It may also be a conjugate, for example an antibody-drug conjugate. Other suitable types of test compounds may also be used in this invention. The method of the present invention may be used for screening. The test compound does not necessarily have to be a single compound. In some cases, a mixture of compounds may be used in the screen. For example, In some embodiments, the extract or fraction thereof, such as a Traditional Chinese Medicine (TCM) extract, is It can be used as a test compound 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 product. In some embodiments, the test compound may be a drug (a Chinese herbal medicine or a Chinese herbal medicine extract). are β-lactam antibiotics, aminoglycoside antibiotics, and tetracycline antibiotics. Chloramphenicol antibiotics, macrolide antibiotics, glycopeptide antibiotics Substances, quinolone antibiotics, nitroimidazole antibiotics, rifamycin antibiotics , echinocandin antibiotics, polyene antibiotics, pyrimidine antibiotics, arylamine The antibiotics may include a benzodiazepine antibiotic, an azole antibiotic, or a combination thereof.

[0078] In some embodiments, the test compound is a β-lactam antibiotic, e.g., a penicillin. , cephalosporins, thienamycins, monobactams, β-lactamase inhibitors, methoxypenicillins, etc.; aminoglycoside antibiotics, such as streptomycin, amikacin, tobramycin, amikacin, neomycin, ribomycin tetracycline antibiotics, such as tetracycline, micronomycin, azithromycin, etc.; Lacycline, oxytetracycline, chlortetracycline, and doxycycline Chloramphenicol antibiotics, such as chloramphenicol, thiamphenicol, etc. macrolide antibiotics, such as erythromycin, leucomycin, odorless erythromycin, Thromycin, acetylspiramycin, medimycin, josamycin, azithromycin glycopeptide antibiotics, such as vancomycin, norvancomycin, tetracycline, icoplanin, etc.; quinolone antibiotics, such as norfloxacin, ofloxacin, cyproheptan-1, cyproheptan-2, cyproheptan-3, cyproheptan-4, cyproheptan-5, cyproheptan-6, cyproheptan-7, cyproheptan-8, cyproheptan-9, cyproheptan-11, cyproheptan- rofloxacin, pefloxacin, gatifloxacin; nitroimidazole antibiotics, For example, metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics e.g., rifampicin; echinocandin antibiotics; polyene antibiotics; pyrimidines Antibiotics; Arylamine antibiotics; Azole antibiotics; Other antibiotics: Fosfomycin Syn, capreomycin, cycloserine, lincomycin, clindamycin, mit mycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazide It may also contain one or more of dinamide, cyclosporine, and the like.

[0079] In some embodiments, the test compound is an insect antimicrobial peptide, e.g., a lepidopteran antimicrobial peptide. Chids, Diptera antibacterial peptides, Coleoptera antibacterial peptides, Odonata antibacterial peptides, Hymenoptera Antibacterial peptides, such as silkworm antibacterial peptides; mammalian antibacterial peptides, such as porcine antibacterial peptides Antimicrobial peptides, sheep antimicrobial peptides, bovine antimicrobial peptides, human antimicrobial peptides, etc.; amphibian antimicrobial peptides Chid: Xenopus, etc.; antibacterial peptides derived from fish, mollusks, and crustaceans: Minami Pardachirus pavoninus antibacterial peptides, catfish ( parasilurus asotus) antimicrobial peptide, mussel antimicrobial peptide, shrimp Antibacterial peptides, etc.; Plant antibacterial peptides: Thionin, etc., bacterial antibacterial peptides peptide: one or more of bacitracin, gramicidin, polymyxin, and nisin may include:

[0080] In some embodiments, the test compound is Utankoboku (Calcined ancie nt ink), Salvia Miltiorrhiza, and Nanshiso ( Arnebia euchroma), Banlancon (Radix Isatidis) , Houttuynia, Honeysuckle, Rhizoma Coptis, Scutellaria, and Hoko Dandelion, Purslane, Hawtho rn), Atlantic Forsythia (Isatidis Folium), Forsythia (Fructu s Forsythiae), Inchin (Herba Artemisiae Capi) llaris), Andrographis Paniculata N ees), Radix Bupleuri, Rhubarb, Euphorbia humifusa, Stemonae, Garlic, Cortex Phellodendri, Horse Chestnut Eucommia, Cortex Fraxini, Jasmine Fructus Cnidii), Galla Chinensis, Deer Viola yedoensis makino, Ubai (Fructus Mume), Licorice (Radix Glycyrrhizae), Sekiryuhi (P ericarpium Granati), Schisandra chine nsis), Spina gleditsiae, oak (Termina lia Chebula), Sophora flavescens, Dokei Cortex Pseudolaricis, Epimedium ), one or more of the following species: Artemisia apiacea Hance It may also include extracts or fractions thereof.

[0081] The above screening method may be a low, medium or high throughput screening method. Typically, multiple test compounds can be screened. In embodiments, the screening method involves screening one or more test compounds in parallel. (including tests conducted substantially simultaneously), for example, 10 or more types, 100 or more types In some cases, 1000 or more compounds may be screened in parallel. In some embodiments, multiple test compounds may be tested. When screening for a compound, the plurality of test compounds may be selected from known broad-spectrum antibiotics. or at least one that is not a known antibiotic effective against one or more species of said microorganisms. In some embodiments, the plurality of test compounds may include at least one test compound. ampicillin, vancomycin, neomycin, metronidazole or tetracycline In some embodiments, the test compound may include at least one test compound that is not phosphorus. The test compound may be a known broad-spectrum antibiotic or a compound active against one or more species of said microorganism. For example, in some embodiments, the test compound is not a known antibiotic. Ampicillin, vancomycin, neomycin, metronidazole, or tetracycline isn't it.

[0082] In some embodiments, the test compound may comprise an anti-inflammatory compound. The article may include an ophthalmic compound known in the art. In some embodiments, an anti-inflammatory compound The substance may be a steroidal or non-steroidal anti-inflammatory compound, a plant extract or fraction of an extract, or It may also include combinations of these.

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

[0084] In some embodiments, the present invention provides a method for producing an animal model, the method comprising: and / or introducing said inactivated microbial protein into the intraocular space of the animal's eye. Microorganisms are usually more prevalent in the intraocular space (e.g., in the ocular cavity) of subjects with ocular disease than in healthy subjects. For example, aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body and ciliary muscle, vitreous humor in the posterior chamber, retina, choroid Eye diseases include cataracts, age-related eye diseases, and glaucoma. Macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt, Koyanagi The induction is selected from the group consisting of vein-keratitis (VKH), endophthalmitis (EOS), and a combination thereof. In some embodiments, the method induces one or more symptoms of an ocular disease. and determining one or more microbial species that are concentrated in the intraocular space of subjects suffering from ocular disease. or determining whether the eye disease is age-related macular degeneration (AMD), Bechet's disease, or Vogt's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt's disease Koyanagi-Harada syndrome (VKH) and combinations thereof.

[0085] In some embodiments, the method may introduce a live microorganism into the intraocular space of the animal's eye. In some embodiments, the method includes inactivating proteins of a microorganism, e.g., ultrafiltration of proteins from a microorganism. The sonolytic protein may be introduced into the intraocular space of the animal's eye. The subject and the animal may be the same or different. For example, in some embodiments In the case where the eye disease is a disease of a pet animal, the subject and the animal may be the same. In some embodiments, the ocular disease may be a human disease, i.e., the subject is a human subject. , and the animal is preferably a non-human mammal, more preferably a non-human primate (e.g. In some embodiments, the animal has similar eye anatomy and structure to humans. and / or the intraocular environment. Preferably, the microorganisms and / or inactivated proteins derived from said microorganisms. The animals were free of eye disease prior to introduction of the substance.

[0086] AMD animal models In some specific embodiments, the present invention provides methods for producing an AMD animal model. In some embodiments, the methods comprise introducing a microorganism and / or an inactivated protein derived from the microorganism into the intraocular space of the animal's eye. Typically, the microorganism comprises a species that is more concentrated in the intraocular space (e.g., aqueous humor, suspensory ligament, ciliary body, ciliary body-ciliary muscle in the anterior chamber, vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject suffering from AMD than in a healthy subject, and the introduction induces one or more symptoms of AMD. Unless otherwise indicated in the context, the microorganism introduced into the intraocular space of the animal is a live microorganism. In some embodiments, the microorganism is selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, and Enterococcus faecalis. Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the microorganism comprises Bacillus megaterium and / or Pseudomonas putida. In some embodiments, the microorganism comprises at least Bacillus megaterium. In some embodiments, the microorganism is a substantially biologically pure population of Bacillus megaterium. In some embodiments, the microorganism comprises a mixture of microbial species, the microbial species being substantially similar to those observed in the aqueous humor, vitreous humor, and / or soft drusen of a subject suffering from age-related macular degeneration. In some embodiments, the microorganism is derived in part or in whole from the aqueous humor and / or vitreous humor of a subject suffering from age-related macular degeneration. For example, in some embodiments, the microorganism may be obtained by culturing a sample obtained from the aqueous humor and / or vitreous humor 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 ocular anatomy and / or intraocular environment similar to that of a human. In some embodiments, the animal is a rhesus monkey, such as a cynomolgus monkey. In some embodiments, the animal is not a rhesus monkey. In some embodiments, the animal is not a cynomolgus monkey.

[0087] The microorganism and / or the inactivated protein derived from said microorganism is introduced into any suitable intraocular space of an animal. In some embodiments, the microorganisms and / or inactivated proteins derived from said microorganisms may be added. Proteins are injected into the subretinal space of animals. Typically, microorganisms and / or proteins derived from said microorganisms are inactivated. The protein is injected into the eye of the animal, although other delivery methods are suitable.

[0088] Typically, the microorganism and / or inactivated protein derived from said microorganism is a compound that inhibits one or more symptoms of AMD. For example, as shown in the Examples section, the amount and concentration of the IL-1 receptor agonist is about 200 mg / mL. 20 CFU of bacteria in 0 μL PBS solution can cause one or more symptoms of AMD, such as dulce de saccharin (Dulce de Saccharomyces cerevisiae). In some embodiments, the microorganism and / or the microorganism-derived The inactivating protein is introduced in a certain amount and concentration, which amount and concentration induces: 1) drusenoid lesions, e.g., in the retinal tissue of animals; 2) e.g., in the eyes of animals; 3) Cases of drusen-like nodules below the retinal pigment epithelium in the For example, pyroptosis of retinal pigment epithelial cells in animal eyes; 4) activation of the complement system in animal eyes. Activation and / or inflammation, e.g., C5A, CFH, caspase 1, and NLRP3 proteins 5) increased expression of activated IL-1β and IL-1β by retinal pigment epithelial cells in animal eyes; and / or IL-18 secretion; or 6) any combination of 1)-5).

[0089] The animals used in the method for producing the animal model of the present application are preferably healthy animals, e.g., The animal is free of eye disease before the introduction of the substance and / or the inactivated protein derived from the microorganism. Preferably, the microorganism and / or the protein derived from said microorganism is / are not introduced into the host. Any antibiotics administered to animals during this period, e.g., before one or more symptoms of AMD appear. do not have.

[0090] In some embodiments, the method for producing an AMD animal model comprises administering to a subject suffering from AMD. into the intraocular space of the animal's eye, wherein the sample The subject's intraocular space is obtained, and the introduction induces one or more symptoms of AMD. In this embodiment, the sample is incubated in a culture medium and optionally In some embodiments, the method further comprises administering to a subject a therapeutically effective amount of the compound. A microscope for obtaining samples from the intraocular space, such as aqueous humor, vitreous humor, and / or soft drusen. The method further comprises step 1) of incubating the sample in a 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 humor of a subject suffering from AMD. In some embodiments, the sample is obtained from soft drupelets of a subject suffering from AMD. As shown in the Examples section of this application, the incubation of the samples is To avoid contamination with microbial species not present in the initial sample from the subject, the sample is usually prepared in a sterile environment ( The procedure is carried out in a sterile medium (e.g., in a closed environment).

[0091] Typically, the method for producing an AMD animal model involves inducing one or more AMD symptoms in an animal that can be sustained for a predetermined period of time. For example, in the absence of intervention, the animal models generated by the methods of the present application typically 1 week, 1 month, or over the lifespan of the animal. Animal models generated by the methods of the present application are also novel features of embodiments of the present invention.

[0092] The AMD animal model generated herein may also be used to identify candidate therapeutic agents for treating or preventing AMD. For example, in some embodiments, the present invention further provides screening methods. The screening method comprises administering a comprehensive test compound to the AMD animal model of the present application. and step b) determining the severity of one or more symptoms of the eye disease after administration. and optionally, a candidate therapeutic agent that alleviates at least one of said symptoms relative to a control. and c) identifying the test compound as compared to the control. 1) For example, by administering the substance, drusenoid lesions in the retinal tissue of animals are reduced. 2) reducing drusen-like nodules below the retinal pigment epithelium, for example, in animal eyes. 3) reduce pyroptosis of retinal pigment epithelial cells in animal eyes; 4) Reduces activation of the complement system and / or inflammation in the eye of an animal, e.g., C5A, CFH, 5) reducing the expression of caspase 1 and NLRP3 proteins in the eyes of animals Decreasing secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells or 6) any combination of 1)-5). may be identified as a candidate therapeutic agent for treating or preventing AMD. In this case, administration of the test compound results in an improvement in the eye (e.g., killing or otherwise affecting microorganisms in the blood and / or gastrointestinal tract, e.g., the intestine; and such test compounds are also candidates for treating or preventing AMD. In some embodiments, the relevant information for the "control" may be In some embodiments, the information may be information observed in animals before administering the compound. The relevant information for the "control" may be that observed in placebo-treated animals, e.g. A placebo formulation containing no test compound is administered.

[0093] The test compounds used in the screening method using the AMD animal model (described above) are not restricted. Preferably, but not limited to, the test compound is administered to subjects suffering from AMD compared to healthy controls. Effectively kills microorganisms (e.g., Bacillus megaterium) that accumulate in the intraocular space of patients or as being capable of inhibiting the growth of the Test compounds are pre-screened by any suitable route, They may be administered according to any study dosing protocol and at any suitable study dose, including: One skilled in the art may select one based on factors such as the potency (if known) of the test compound. For example, the test compound may be administered orally, topically, intravitreally, intramuscularly, subcutaneously, or intravenously. Good too.

[0094] Screening methods using AMD animal models (described above in this application) typically involve patients with low to moderate thromboembolism. In some embodiments, multiple test compounds are screened. The plurality of test compounds are selected from known broad-spectrum antibiotics or At least one test compound that is not a known antibiotic effective against one or more species of In some embodiments, the plurality of test compounds includes ampicillin, vancomycin, benzodiazepine, benzocaine, benzophenone, benzocaine ... At least one that is not cyclosporine, neomycin, metronidazole or tetracycline In some embodiments, the test compound comprises a known broad-spectrum is not a steroid antibiotic or a known antibiotic effective against one or more species of said microorganisms. For example, in some embodiments, the test compound is ampicillin, vancomycin, Not neomycin, metronidazole or tetracycline.

[0095] In some embodiments, the present invention provides a method for producing a mammalian model of an eye disease, the method comprising: comprises one or more microorganisms and / or one or more inactivated proteins of said one or more microorganisms. and introducing the antibody into a mammalian eye to create a mammalian model. In some embodiments, the method further comprises monitoring the onset and progression of one or more markers of eye disease. Markers for eye diseases may include those biological and genetic information known in the art that is associated with a given disease. and / or chemical markers, including but not limited to symptoms of eye disease. In some embodiments, the step of monitoring the onset and progression of one or more markers of eye disease comprises administering to a mammalian animal. In some embodiments, the method may include monitoring an inflammatory response in the eye of a mammal. The step of monitoring the onset and progression of one or more markers of drusenoid lesions may include monitoring the onset and progression of drusenoid lesions. In some embodiments, the method may include monitoring the mammal for dulce de saccharin. In order to develop idiopathic lesions, the one or more microorganisms and / or the one or more microorganisms The method further comprises the step of allowing a sufficient time to elapse after introducing one or more inactivated proteins. In some embodiments, the one or more microorganisms and / or one of the one or more microorganisms The step of introducing one or more inactivated proteins may be carried out by introducing one or more of the microorganisms or one or more of the inactivated proteins. This may involve intraocular injection of inactivated proteins of one or more of the above microorganisms. In embodiments, the intraocular injection may include injection into the vitreous humor or aqueous humor of the mammal.

[0096] Treatment method In some embodiments, the present invention further provides methods of treating or preventing AMD. In some embodiments, the methods include administering to a subject in need thereof an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the methods include administering to a subject in need thereof an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the methods include administering to a subject, for example, intraocular space, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythroides, Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the method comprises identifying or having identified the subject as infected, e.g., in the intraocular space, with Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium, and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the method includes infecting, for example, into the intraocular space, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, FaeciumThe method includes the steps of selecting a subject infected with one or more species selected from Bacillus megaterium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the method includes the steps of selecting a subject infected, e.g., in the intraocular space, with Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium, and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified by any of the screening methods herein. In some embodiments, the subject does not suffer from Behçet's disease (BD), cataracts (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, the method of treating or preventing AMD includes administering to a subject, for example, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Enterococcus faecalis, Lactobacillus subtilis ... FaeciumThe method includes identifying or having identified the subject as infected with one or more species selected from Bacillus megaterium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering an effective amount of an antibiotic to the subject. As used herein, an antibiotic generally refers to a compound with antibacterial activity, and may be naturally occurring or synthetic. Several antibiotics are included herein. In some embodiments, the method includes identifying or having identified the subject as infected with Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium, for example, in the intraocular space, and administering an effective amount of an antibiotic to the subject. In some embodiments, the method includes infecting, for example, into the intraocular space, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, FaeciumThe method includes the steps of selecting a subject infected with one or more species selected from Bacillus megaterium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae, and administering an effective amount of an antibiotic to the subject. In some embodiments, the method includes the steps of selecting a subject infected with, for example, Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium, in the intraocular space, and administering an effective amount of an antibiotic to the subject. In some embodiments, the method includes the steps of selecting a subject infected with, for example, Bacillus megaterium, in the intraocular space, and administering an effective amount of an antibiotic to the subject. In some embodiments, the subject does not suffer from Behçet's disease (BD), cataracts (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the subject suffers from AMD. In some embodiments, the subject has not been diagnosed with AMD. In some embodiments, the subject is at risk for developing AMD. Administration is not limited to any particular route and may be, for example, oral, topical, intravitreal, intramuscular, subcutaneous, and / or intravenous. In any embodiment of the present application, an "effective amount" of an antibiotic may be an amount that effectively kills or inhibits the growth of one or more microbial species in the eye of the treated subject, where the one or more microbial species are enriched in AMD patients compared to healthy controls, e.g., the one or more microbial species may be Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium.

[0098] In some embodiments, the present invention provides for the following in a subject in need thereof: Further provided are methods for: 1) reducing drusenoid pathology, e.g., in retinal tissue; 2) reducing drusen-like nodules below the retinal pigment epithelium, for example in the eye; 3) 4) reducing pyroptosis of retinal pigment epithelial cells in the eye; and 5) inhibiting the complement system in the eye. Reduce activation and / or inflammation, e.g., C5A, CFH, caspase 1, and NLR 5) Reducing the expression of P3 protein by retinal pigment epithelial cells in the eye. 6) reducing the secretion of IL-1β and / or IL-18, or 6) any combination of 1)-5). The method is directed to a combination of a medicament for AMD identified by any of the screening methods of the present application. In some embodiments, the method further comprises administering to the subject an effective amount of any candidate therapeutic agent. The present invention provides a method for treating drusen symptoms (e.g., soft drusen) in a subject in need thereof. The present invention further provides a method for treating a cancer, which comprises the steps of: The method includes administering to the subject an effective amount of any candidate therapeutic agent for AMD that has been identified. Drusen symptoms (e.g., soft drusen) are caused by microbial infections, such as the pathogenic bacteria of the present application. Drusen symptoms (e.g., soft drusen) may be induced by AMD. The term may also refer to subjects undergoing

[0099] In some embodiments, the present invention provides for the following in a subject in need thereof: Further provided are methods for: 1) reducing drusenoid pathology, e.g., in retinal tissue; 2) reducing drusen-like nodules below the retinal pigment epithelium, e.g., in the eye; 1) Reducing pyroptosis of retinal pigment epithelial cells in the eye, 4) Inhibiting the complement system in the eye Reduces activation and / or inflammation of, for example, C5A, CFH, caspase 1, and NL 5) downregulating the expression of RP3 protein by retinal pigment epithelial cells in the eye Decreasing the secretion of IL-1β and / or IL-18, or 6) any of 1)-5). The method includes administering to a subject an effective amount of an antibiotic, for example, In some embodiments, the method reduces drusenoid pathology 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 eye of the subject. In some embodiments, the method includes activating the complement system and / or inflammation in the eye of the subject. In some embodiments, the method reduces retinal pigment epithelial cell proliferation in the eye of the subject. It reduces the secretion of active IL-1β and / or IL-18 by cells. The antibiotics are intended to kill bacteria (e.g., pathogenic bacteria) in the intraocular space of the subject, without the hope of causing serious eye damage. and killing or inhibiting the growth of the inflammatory cytokines, thereby preventing or preventing the development of inflammatory cytokines, such as inflammatory cytokines, in subjects suffering from AMD. may reduce drusen formation, drusenoid lesions and / or drusen-like nodules in As is apparent from the present application, AMD is caused by one or more pathogenic microorganisms (e.g., Bacillus It is associated with infection with bacteria (S. megaterium and / or Pseudomonas putida). Protozoan microorganisms, such as those described herein, e.g., Bacillus megaterium and / or Pseudomonas aeruginosa. It is thought that Domonas putida can induce inflammation in the eye. Antibiotics that can kill or inhibit the growth of pathogenic microorganisms are administered to subjects (e.g., those with AMD). In some embodiments, the present invention may also reduce ocular inflammation in affected subjects. The invention provides a method for treating drusen symptoms (e.g., soft drusen) in a subject in need thereof. Further provided is a method of treating, the method comprising administering to a subject an effective amount of an antibiotic. Drusen conditions (e.g., soft drusen) can be caused by microbial infections, such as those described herein. Drusenic symptoms (e.g., soft drusen) may be present in patients with AMD. In some embodiments, the method may involve a subject having drusenoid lesions. and / or reduce nodules.

[0100] In some embodiments, the present invention provides for the following in a subject in need thereof: Further provided are methods for: 1) reducing drusenoid pathology, e.g., in retinal tissue; 2) reducing drusen-like nodules below the retinal pigment epithelium, e.g., in the eye; 1) Reducing pyroptosis of retinal pigment epithelial cells in the eye, 4) Inhibiting the complement system in the eye Reduces activation and / or inflammation of, for example, C5A, CFH, caspase 1, and NL 5) downregulating the expression of RP3 protein by retinal pigment epithelial cells in the eye Decreasing the secretion of IL-1β and / or IL-18, or 6) any of 1)-5). The method includes combining a compound of the present disclosure (e.g., 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 I I-10), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3), Formula IV Compound IV-1 or IV-2 (e.g., formula IV-3, formula IV-4, formula IV-5, formula IV-6) a compound selected from the group consisting of a glycoside (e.g., Formula V), compounds 1-8, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt or ester thereof. Pharmaceutical compositions, wherein the aglycone of the glycoside is a phenolic compound, a flavonoid, a kumari The method includes administering to the subject an effective amount of a compound (e.g., a benzoic acid, a sterol, or a benzoic acid). For example, in some embodiments, the method includes administering a therapeutically effective amount of a compound to a subject to reduce drusenoid pathology. In some embodiments, the method reduces drusen-like nodules in a subject. In some embodiments, the method comprises measuring pyroptosis of retinal pigment epithelial cells in the eye of the subject. In some embodiments, the method reduces the activity of the complement system in the eye of the subject. In some embodiments, the method reduces inflammation and / or inflammation in the eye of the subject. It reduces the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells. Without wishing to be bound by theory, the compounds of the present disclosure may be used to inhibit, for example, cell proliferation in the intraocular space of a subject. Kill or inhibit the growth of bacteria (e.g., pathogenic bacteria), thereby preventing, e.g., AM Drusen formation, drusenoid lesions and / or drusen-like lesions in subjects with D It is believed that AMD may be caused by one or more pathogenic factors. Infection with microorganisms (e.g., Bacillus megaterium and / or Pseudomonas putida) Also, pathogenic microorganisms, such as those described herein, e.g., Bacillus megaterii, It is thought that Pseudomonas putida and / or Pseudomonas putida can induce ocular inflammation. Thus, compounds of the present disclosure that kill or inhibit the growth of pathogenic microorganisms to which they are administered It can also reduce ocular inflammation in a subject (e.g., a subject suffering from AMD). In some embodiments, the present invention provides a method for treating drusen symptoms (e.g., drusen-associated inflammatory bowel disease) in a subject in need thereof. Further provided is a method of treating a vascular endothelial cell carcinoma (e.g., soft drusen) comprising administering a compound of the present disclosure to a subject. The method includes administering an effective amount to an examiner. Drusen symptoms (e.g., soft drusen) can be treated by It may be induced by a microbial infection, such as the pathogenic bacteria of the present application. Drusen (e.g., soft tissue) Drusen may be associated with a subject suffering from AMD. The method reduces drusenoid lesions and / or nodules.

[0101] There are no particular limitations on subjects suitable for treatment with the methods of the present application. In some preferred embodiments, the subject has AMD. In some embodiments, the AMD may be dry or wet age-related macular degeneration with drusen symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), e.g., 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 for developing AMD. In some embodiments, the subject has soft drusen deposited between the retinal pigment epithelium (RPE) and Bruch's membrane. In some embodiments, the subject has retinal pigmentary 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 with one or more species in the intraocular space that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein. In some embodiments, the subject is infected with one or more species in the intraocular space that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein. In some embodiments, the subject is infected with one or more species in the intraocular space that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein. FaeciumIn some embodiments, the subject is infected with one or more species selected from Bacillus megaterium, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the subject is infected in the intraocular space with Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium. In some embodiments, the subject is infected with Behcet's disease (BD), cataracts (Cat), endophthalmitis, or other conditions. The subject does not suffer from EOS, glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the method may further comprise the step of identifying or having identified the subject as infected with one or more species that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein. In some embodiments, the method may comprise the step of identifying the subject as infected with, or having identified, one or more species that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein above. In some embodiments, the method may comprise the step of identifying the subject as infected with, or having identified, one or more species that are more concentrated in the intraocular space of AMD patients than in healthy subjects, for example, as described herein above. Faecium In some embodiments, the method may further comprise identifying or having identified the subject as infected with one or more species selected from the group consisting of Bacillus megaterium, Bacillus licheniformis, and Xanthomonas oryzae. In some embodiments, the method may further comprise identifying or having identified the subject as infected with Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium, in the intraocular space.

[0102] The administration of antibiotics is not limited to any particular route of administration. For example, administration can be oral, topical, or The administration may be intravitreal, intramuscular, subcutaneous and / or intravenous. In embodiments, antibiotics are administered by intravitreal injection, e.g., intravitreal depot injection or intravitreal implantation. In some embodiments, more than one route of administration (e.g., oral and intravitreal) is used. For example, in some embodiments, the antibiotic is They may be administered orally and intravitreally simultaneously or sequentially in any order. In this embodiment, the antibiotics are administered orally and intravenously simultaneously or sequentially in any order. In the case of the same active ingredient or two different active ingredients, it may be combined with other administration routes. Antibiotics may be used in the form of solids, liquids, semi-solids, solutions, suspensions, implants or any other formulation. For example, oral antibiotics are usually available in solid or liquid form. In some embodiments, the antibiotic may be formulated into the implant. In the case of intravenous injection, there are no particular limitations on the injection site. For example, in some embodiments, the injection It may also be injected into the suprachoroidal space. Other suitable sites are known in the art. An effective amount is Several factors, such as time of administration, route of administration, duration of treatment, efficacy of antibiotics (e.g., health Kill or inhibit the growth of one or more microorganisms that concentrate in the intraocular space compared to healthy controls (injurious to the immune system), which may vary depending on its clearance and whether other medications are administered concomitantly. Multiple antibiotics, such as any one of these antibiotics described herein, and Antibiotics described in PCT / CN2019 / 070572 filed on January 7, 2019 Any one of the patents may be used in the method of the present application, the contents of which are incorporated by reference in their entirety. and is incorporated herein by reference.

[0103] In some embodiments, the antibiotic is a β-lactam antibiotic, an aminoglycoside antibiotic, or Biological substances, tetracycline antibiotics, chloramphenicol antibiotics, macrolides antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics Biosubstances, rifamycin antibiotics, echinocandin antibiotics, polyene antibiotics, Pyrimidine antibiotics, allylamine antibiotics, or azole antibiotics, or any of these It may also be a combination.

[0104] In some embodiments, the antibiotic is a β-lactam antibiotic, such as a penicillin ( For example, penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafsili penicillin, oxacillin, penicillin G, piperacillin, pivampicillin, pivmecillinam, Carcillin, cephalosporins such as cefastril, cefadroxil, cephalexin Cephaloglycin, Cephalonium, Cephaloridine, Cephalothin, Cefapyridine Cefatrizine, cefazaflur, cefazedone, cefazolin, cephradizine, Floxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cef Onicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, Cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime , cefteram, ceftibuten, ceftiofur, ceftaroline, ceftizoxime, ceftri Axon, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam , cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, cefta Lorin, cefacromedine, cephaloram, cefparole, cefcanel, cefedrol , cefenpidon, cefetrizole, cefibitril, cefmatilen (cefmati len), cefmepidium, cefovecin, cefoxazo Cefurotil, cefsumid, cefratime, ceftioxide, thienamycins, mono Bactams, β-lactamase inhibitors, methoxypenicillins; aminoglycosides Substances such as streptomycin, gentamicin, kanamycin (e.g. A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin Isomycin C, Neomycin E), Ribomycin, Micronomycin, Azithromycin, Dimethicone Bekacin, sisomicin, netilmicin, paromomycin, bramycin, etc.; Tetrasamine Icrine antibiotics, such as tetracycline, oxytetracycline, chlortetracycline cycline, doxycycline, and the like; chloramphenicol antibiotics, such as chloramphenicol thiamphenicol, thiamphenicol, etc.; macrolide antibiotics, such as erythromycin Syn, leucomycin, odorless erythromycin, acetylspiramycin, medimicin thromycin, josamycin, azithromycin, clarithromycin, dirithromycin, loxacin cysthromycin, telithromycin, etc.; glycopeptide antibiotics, such as vancomycin quinolone antibiotics, such as norfloxacin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, such as norfloxacin ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, eno fluoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, such as metronidazole and tinidazoline rifamycin antibiotics, such as rifampicin; echinococcus Polyene antibiotics; Pyrimidine antibiotics; Arylamine antibiotics azole antibiotics; other antibiotics: fosfomycin, capreomycin, cyclomycin Serine, lincomycin, clindamycin, mitomycin, actinomycin D, leomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymyxin Polymyxin B combinations, such as polymyxin B / trimethoprim, polymyxin B / bacitra It may contain one or more of the following: erythromycin, polymyxin B, neomycin, gramicidin, etc.

[0105] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, sarcoid Lubarsan, azithromycin, azlocillin, aztreonam, bacitracin, capret Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Phallothin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, clopidogrel Ramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin fluticasone, clofazimine, cloxacillin, colistin, cycloserine, dalfopristine dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, Xicycline, erythromycin, ethambutol, ethionamide, flucloxacillin fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isononyl Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, metronidazole Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupirone Leucine, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin penicillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Rifabutin, rifampicin, rifamycin fampin), rifapentine, rifaximin, roxithromycin, sulfadia Silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavan Telavancin, telithromycin, temocillin, tetracycline, Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, troleandomycin, vancomycin, enoxacin, lomefloxacin cin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moxa Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicid, Falazine, cephapirin, cephalothin, cefmetazole, cefotaxime, moxara Cettam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Radezolid zolid, Torezolid, Oritavancin ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Teixobactin, Malacidins and A combination of these may be selected.

[0106] In some embodiments, the present invention provides a method for treating or preventing AMD using any of the methods described herein. A candidate therapeutic agent identified by the screening method of the present invention, or a pharmaceutical composition containing the candidate therapeutic agent. More to offer.

[0107] compound In some embodiments, the present disclosure provides a method for the detection of AMD-associated microorganisms, such as Bacillus megateri. A compound containing a plurality of compounds capable of killing or inhibiting the growth of bacteria and / or bacteria. The present invention relates to a composition comprising:

[0108] The compounds of the present application typically have antibacterial activity by themselves or in combination with another agent. The compounds may be bactericidal or bacteriostatic. Multiple compounds may be used in embodiments of the present invention. For example, in some embodiments, The compounds of the present application may be used in combination with any alcohol, phenol, or the like known to have antibacterial activity. compounds, amines, sulfonamides, quinolones, anthraquinones and / or benzoates Non-limiting examples of useful compounds include benzoic acid, benzyl alcohol, and related compounds of aromatic acid. Alcohols, coumarins, catechols, polyphenols, chalconoids (liquocalco stilbenes (including resveratrol, isoresveratrol, etc.), phenols Nolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechu Acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acids, caffeic acids, ferric acid, carboxylic acids, chlorogenic acid, sinapic acid, flavonoids such as catechin, naringenin, Quercetin, rutin, chrysin, etc., tannins such as ellagic acid, and esters thereof This includes glycosides and their glycosides.

[0109] The characteristics of the compounds of the present application are usually some functional groups present in their molecular structure. In some embodiments, the compounds of the present application are characterized by the presence of an alcoholic hydroxyl group, a phenolic hydroxyl group, or groups and / or carboxylic acid groups or derivatives thereof, such as esters, amides, carbonate esters The main features of the present invention are the presence of hydroxybenzoates, carbamates, sulfonates, glycosides, etc. In some embodiments, amino groups, sulfonamide groups, thiol groups, and / or sulfoxide groups Compounds having a group or a sulfone group may also be used in the compositions and methods of the present application.

[0110] The compounds of the present application may have a polycyclic, bicyclic or monocyclic core structure, Any of the groups may be substituted with one or more of the groups described herein.

[0111] In some embodiments, the compounds of the present application have the formula I or a pharmaceutically acceptable salt or ester thereof. The present invention may be characterized by having the following. JPEG0007799657000001.jpg4159. For the avoidance of doubt, in Formula I, the cyclic structure Cy 1 and another cyclic structure Cy 2 There are two Ringer L and L’ and the two cyclic structures may be identical. The two ringers may be different. 1 and Cy 2 Forms another ring structure between In addition, Cy 1 and Cy 2 are L and L respectively. ’ It is a ring structure independent of In formula I, Cy 1 and Cy 2 each independently represents an optionally substituted cycloalkyl ring ( For example, C 3-7 cycloalkyl ring), optionally substituted heterocycles, e.g., optionally substituted 4-7 membered heterocycles (e.g., one or two cyclohexyl groups independently selected from N, O, and S) having a heteroatom), an optionally substituted aromatic ring (e.g., C 6-10 Aromatic rings (e.g., fluorine) a phenyl group) or an optionally substituted heteroaromatic ring, such as an optionally substituted 5-10 membered heteroaromatic ring; Aromatic rings (e.g., 5- or 6-membered heteroaromatic rings, independently selected from N, O, and S) a heteroaromatic ring having one or two cycloheteroatoms, L and L ’ are each independently empty or ringer (e.g., as described herein), When used herein, the term "ringer" is not intended to be limited to any particular type of linking group. For example, in some embodiments, Ringer is not a single moiety to which it is attached. A ring structure may be formed, for example, by combining L and Cy. 1 Cy 2 independently form a ring structure Also, L 2 is empty, may be replaced C 1-6 Alkylene group, optionally substituted C 1-6 Hetero Alkylene group, optionally substituted C 2-6Alkenylene group, optionally substituted C 2-6 a alkylene group, optionally substituted C 3-6 cycloalkylene group, optionally substituted aryl group an optionally substituted heteroarylene group, an optionally substituted 4- to 7-membered heterocyclohexyl group, may be a rylene group, W is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CO NR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3 d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or JPEG0007799657000002.jpg1818, where: R 1 and R 1a are each independently hydrogen, an optionally substituted alkyl group, a substituted an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted is a good heterocyclic group, R 3 and R 4 are each independently hydrogen, -COR 2b , -SO2R 5b , replaced by Good C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl groups, optionally substituted C2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted a phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- a 7-membered heterocyclic group, or R 3 and R 4 are substituted together with the atoms to which they are attached. forming a 4- to 7-membered heterocyclic group which may be R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 a Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco oxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cyclo an alkoxy 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, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C1 -6Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C3 -6 a cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5- or 6-membered phenyl group; or an optionally substituted 4- to 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 teeth together with the atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclic group. Cy in Formula I 1 and Cy 2 may be an aromatic or non-aromatic ring system, and in some cases, In a preferred embodiment, Cy in Formula I 1 and Cy 2 Of At least one of the rings is an aryl group or a heteroaromatic ring, for example, an optionally substituted C 6-10 aroma ring, or an optionally substituted 5-10 membered heteroaromatic ring. For example, in some embodiments, So, Cy 1 and Cy 2 does not represent any substituents that are the core structure of Formula I The structure of JPEG0007799657000003.jpg1822 can be either of the following: JPEG0007799657000004.jpg78122, where L 2 -W may be connected to the left or right ring, where L and L ’ is the original It may be any one of the above, and suitable substituents for use on the ring are described herein. do.

[0112] In some embodiments, Cy in Formula I 1 and Cy 2 are all aryl or heteroaromatic groups. For example, in some embodiments, the compound of Formula I has the formula I-1: That's fine. JPEG0007799657000005.jpg4558.

[0113] In some embodiments, Ar in Formula I-1 1 and Ar 2 are each independently substituted C 6-10 It is an aromatic ring or an optionally substituted 5- to 10-membered heteroaromatic ring. In some embodiments, Ar in Formula I-1 1 and Ar 2 are each independently substituted The aromatic ring may be a benzene ring or a 5- or 6-membered heteroaromatic ring. In this embodiment, Ar in formula I-1 1 and Ar 2 are each independently an optionally substituted benzene an optionally substituted thiophene ring, an optionally substituted furan ring, an optionally substituted pin ring, It is a lysine ring or an optionally substituted pyrimidine ring. Formula I-1 typically has a polycyclic core structure. For example, in some embodiments, Ar 1 Reach and Ar 2 does not represent any substituents that are the core structure of formula I-1 Allow JPEG0007799657000006.jpg1822 to be any one of the following: JPEG0007799657000007.jpg92170, where L 2 -W may be connected to the left or right ring, where L and L ’ is the original wish The definitions and descriptions of suitable substituents for the rings are given herein.

[0114] In some embodiments, the compound of formula I may have formula I-2. JPEG0007799657000008.jpg3058, During the ceremony, m is 0, 1, 2 or 3; R 10 Each occurrence of represents independently a halogen, L 2’ -W ’ , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Archi C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloal alkyl group, optionally 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- to 7-membered heterocyclic group or two adjacent R 10 , or one R 10 and L or L ’ These are together with the atom to which it is bonded, an optionally substituted cycloalkyl group, heterocyclic group, aryl group, or Forming a heteroaromatic ring, where -L 2’ -W ’ is chosen independently each time it appears, and L 2’ may be independently replaced by an empty C 1-6 Alkylene group, substituted C 1-6 Heteroalkylene group, optionally substituted C 2-6 alkenylene groups, C which may be substituted 2-6 Alkynylene group, optionally substituted C 3-6 Cycloalkylene a group, an optionally substituted arylene group, an optionally substituted heteroarylene group or a substituted is an optionally 4- to 7-membered heterocyclylene group, and W ’ appears independently each time -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 JPEG0007799657000009.jpg1818, where 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 is defined herein, see for example Formula I. In addition, the structural unit -L 2’ -W ’ and -L 2 Each instance of -W is chosen independently, and They may be the same or different.

[0115] In some embodiments, Cy in Formula I-2 1is an optionally substituted benzene ring, an optionally substituted thiophene ring, an optionally substituted furan ring, an optionally substituted pyridine ring, or In some embodiments, Cy in Formula I-2 is an optionally substituted pyrimidine ring. 1 teeth , may be replaced by C 3-6 a cycloalkyl ring or an optionally substituted 4-7 heterocycle; The heterocycle may contain one or two cycloheteroatoms independently selected from N, O, and S. do.

[0116] In some embodiments, Cy 1 is a formula I-2 in which the core structure is one of the following: This will also be possible. JPEG0007799657000010.jpg32116 where -L 2 -W is connected to the right benzene ring, and L and L ’ is defined herein, Suitable substituents for the ring are described herein.

[0117] In a more preferred embodiment, Cy in Formula I 1 and Cy 2 are all benzene rings. For example, in some embodiments, the compound of formula I-2 may have formula I-3. JPEG0007799657000011.jpg2676, During the ceremony, L, L ’ , L 2 , W., R. 10 and m are defined herein, see, for example, Formula I-2: n is 0, 1, 2 or 3; R 11 Each occurrence of represents independently a halogen, -L 2’ -W ’ , optionally substituted C1 -6 alkyl group, optionally substituted C 2-6Alkenyl group, optionally substituted C 2-6 a alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cyclo alkyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted phenyl an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4- to 7-membered heteroaryl group It may be a cyclic group, or two adjacent R 11 , or one R 11 and L or L ’ may be substituted cycloalkyl groups, heterocyclic groups, alkyl groups, alkyl aryl groups, alkyl aryl aryl groups, and alkyl aryl groups, together with the atoms to which they are attached. form an aryl group or a heteroaromatic ring, wherein L 2’ and W ’ is defined herein, See for example the definition of formula I-2, and -L 2’ -W ’ is chosen independently each time it appears. can be. L and L in Formula I (for example, any one of Formulas I-1 to I-3) ’ is, independently, In some embodiments, L and L in Formula I may be empty or ringer. ’ Is that Each independently represents an empty group, -C(O)-, an optionally substituted C 1-4 Alkylene groups, substituted Good C 2-4 Alkenylene groups, -O-, -S-, and -NR 100 -, -S(O)-, -S O2-, -X 1 -G 1 -, -X 2 -G 2 -X 2a -or-CR 101 R 102 - and where: X 1 , X 2 and X 2amay be independently substituted C 1-4 Alkylene groups, substituted Good C 2-4 Alkenylene groups, -O-, -C(O)-, -S-, and -NR 100a -, -S(O)-, -SO2- or -CR 101a R 102a - and G 1 and G 2 may be independently substituted C 1-4 Alkylene groups, optionally substituted C 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 -teeth, Does not contain ON, SS, SN (except SO2-N) or -C(O)-S bonds; R 100 and R 100a are independently a lone pair (if applicable), hydrogen, or C OR 2c , -SO2R 5c , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3- 6-cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered hetero an aryl group or an optionally substituted 4- to 7-membered heterocyclic group, or R 100 or R 1 00a is R 10 or R 11 group to form an optionally substituted heterocyclic or heteroaromatic ring, R 101 , R 101a , R 102 and R 102a are, if present, each independently Hydrogen, -OH, halogen, optionally substituted C 1-6 Alkyl group, optionally substituted C2 -6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 a cycloalkoxy group, an optionally substituted amino group, an optionally substituted phenyl group, a substituted an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- to 7-membered heterocyclic group; , or R 101 and R 102 , or R 101a and R 102a is the combination of these Together with the atoms, form an optionally substituted 3- to 7-membered cycloalkyl group or heterocyclyl ring. or R 101 and R 102 Either one of or R 101a and R 102a One of them is R 10 or R 11 The group may be an optionally substituted cycloalkyl group or heterocyclyl ring. Forming, and R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl groups, C which may be substituted 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, substituted C3-6 cycloalkoxy groups, optionally substituted phenyl groups; optionally substituted an optionally substituted 4- to 7-membered heterocyclic group; or an optionally substituted 5- or 6-membered heteroaryl group. Ringer L or L ’ If forms a double bond with one of the ring carbons, this is R 101 and R 102 CR that exists together 101 R 102 This is because the carbon valence is greater than 4. In such a case, R 101 and R 102 does not exist, and L or L ’ is the CR defined in this application. 101 or CR 102 L or L ’ is the ring carbon If it forms a double bond with one, this is NR 100 where R may be 100 teeth, Typically, it is a lone pair. Other similar situations in this disclosure should be understood similarly. .

[0118] In some embodiments, L and L in Formula I ’ are independently empty, -O-, and -C (O)-, -S-, -NR 100 -, -S(O)-, -SO2- or -CR 101 R 10 2 In some embodiments, the compound of formula I is any of I-4 to I-5. or one of the formulas. JPEG0007799657000012.jpg5295 and JPEG0007799657000013.jpg5198In formula, X 3 , X 4 and X 5 are each independently empty, -O-, -C(O)-, -S-, or -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 the present application. It is defined as follows.

[0119] In some embodiments, the compound has formula I-4, wherein X 3 and X 4 are respectively Independently, -O-, -C(O)-, -S-, and -NR 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 is hydrogen or optionally substituted C 1-4 It is an alkyl group. L in Formula I (e.g., any of the subformulas hereinabove, e.g., Formulas I-1 to I-5) 2 is common Usually, the W group is empty, i.e., Cy 2 In some embodiments, in Formula I, L 2 is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or is C 1-4 It may also be a heteroalkylene group. For example, the W group may be a methylene group or an ethenyl group. Cy via the group 2 may be connected to The plurality of W groups may be of formula I (e.g., any of the subformulas herein above, e.g., formulas I-1 to I-5). In a preferred embodiment, each occurrence of the W group is independently selected from the group -O H, -NH2, -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 alkanoyl), -COOH, JPEG0007799657000014.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), where each C 1-4 Alkyl group independently, C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2, and In some embodiments, the alkyl group may be substituted with 1 to 3 substituents independently selected from fluorine. In the form, W in Formula I is -OH, -NH2, -SO2NH2, -SO2NH(acetyl) , -COOH, JPEG0007799657000015.jpg1818 or -OC(O)-CH3. As described herein, L 2’ -W ’ In some embodiments, Cy 1 or Cy 2 example BaAr 1 or Ar 2 Where applicable, the substituents used in formula I (the present application) may be selected as L in any of the above sub-formulas, including formulas I-1 to I-5 2’ appears every time , e.g., Ar 1 or Ar 2 (if applicable) may be empty independently, W ’ The base is Cy 1 or Cy 2 directly connected to C1-4 Alkylene group, C 2-4 a Alkenylene group, C 2-4 Alkynylene group or C 1-4 Heteroalkylene groups, for example: , W ’ The group can be, for example, Ar 1 or Ar 2 Regarding C, C is connected via a methylene group or an ethenyl group. y 1 or Cy 2 Where applicable, Formula I (or any of the sub-formulae hereinabove) may be connected to , including formulas I-1 to I-5) ’ Each occurrence of represents independently -OH, -N H 2 , -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 a alkanoyl), -COOH, JPEG0007799657000016.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), where each C 1-4 a The alkyl groups are independently C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2 and fluorine. In some embodiments, when applicable, W in Formula I ’ Each instance of is -OH, -NH2 , -SO2NH2, -SO2NH(acetyl), -COOH, It may be JPEG0007799657000017.jpg1818 or -OC(O)-CH3. The multiple groups may be any of the groups of formula I (e.g., any of the sub-formulas hereinabove, e.g., the groups of formula I) that are applicable. In this case, R in formulas I-2 to I-5) 10 and R 11 Some embodiments are applicable to: So, R 10 and R 11 Each occurrence of each of the following may independently be selected from the group consisting of F; Cl; -O H;-NH2;-SO2NH2;-SO2NH(C 1-4 alkyl);-SO2NH(C 1-4 alkanoyl);-COOH; JPEG0007799657000018.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 group, C 1-4 Alkoxy groups, -OH, -NH2, and and fluorine, 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Independent of alkoxy groups, -OH, -NH2, and fluorine C optionally substituted with 1 to 3 substituents selected from 2-6 Alkenyl group; C 1-4 Al kill group, C 1-4 one independently selected from an alkoxy group, —OH, —NH2, and fluorine; C optionally substituted with 3 substituents 2-6 Alkynyl group; C 1-4 Alkyl groups and C optionally substituted with 1 to 3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4substituted with 1 to 3 substituents independently selected from alkyl groups and fluorine; Good C 3-6 a cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH2, and fluorine. Good C 1-4 In some embodiments, R 10 and R 11 Each of, each occurrence, independently represents: -OH; -NH2; -SO2NH2; - SO2NH(C 1-4 alkyl);-SO2NH(C 1-4 alkanoyl);-COOH ; JPEG0007799657000019.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 group; or C 1-4 It may also be an alkoxy group. In some embodiments, R 10 One or more instances of and / or R 11 One of Multiple instances may be independently L as described herein. 2’ -W ’ It is selected from It's okay to have one. Typically, m is 0, 1 or 2, preferably 1, where applicable. Typically, n is 0, 1, 2 or 3, preferably 1 or 2, where applicable.

[0120] In some embodiments, the compounds of the present application have Formula II, or a pharmaceutically acceptable salt or may be characterized by an ester. JPEG0007799657000020.jpg2184, During the ceremony, Cy 10 and Cy 11 are each independently an optionally substituted cycloalkyl ring (e.g., Ba, C 3-7 cycloalkyl ring), optionally substituted heterocycle (e.g., 4- to 7-membered heterocycle) , an optionally substituted aromatic ring (e.g., C 6-10 aromatic ring), optionally substituted heteroaromatic ring (e.g., 5-10 membered heteroaromatic ring), or a cycloalkyl ring or heterocyclic ring and an aryl group or a heteroaromatic ring, and the ring structure may be a fused ring or other form. The two may be connected in the same manner, L 10 is empty or ringer, L 11 is empty, may be replaced C 1-6 Alkylene group, optionally substituted C 1-6 Haitai an optionally substituted C alkylene group; 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted aryl an optionally substituted heteroarylene group, an optionally substituted heteroarylene group, or an optionally substituted 4- to 7-membered heteroarylene group; is a crylene group, W 10 -OR 1 ;-COOR 1a ;-OCOOR 1a ;-COR 2 ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2 NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or JPEG0007799657000021.jpg1818, During the ceremony, R 1 and R 1a are each independently hydrogen, an optionally substituted alkyl group, a substituted an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted is a good heterocyclic group, R 3 and R 4 are each independently hydrogen, -COR 2b , -SO2R 5b , replaced by Good C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl groups, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted a phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- a 7-membered heterocyclic group, or R 3 and R 4 are substituted together with the atoms to which they are attached. forming a 4- to 7-membered heterocyclic group which may be R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , may be replaced by C 1-6 alkyl group, optionally substituted C2-6 a Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco oxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cyclo an alkoxy 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, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C3 -6 a cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5- or 6-membered phenyl group; or an optionally substituted 4- to 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 teeth together with the atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclic group.

[0121] In some embodiments, in Formula II, Cy 10 and Cy 11 At least one of C which may be substituted 6-10 An aromatic ring or an optionally substituted 5- to 10-membered heteroaromatic ring In some embodiments, Cy 11 may be replaced by C 6-10 Aromatic or substituted Cy is a 5-10 membered heteroaromatic ring that may be 11 is a bicyclic or polycyclic aryl group or heterocyclic group If it is an aromatic ring, L 10 -Cy 10 and L 11 -W 10 are independently connected via any ring. Cy 11 In some embodiments, Cy 11 is an aryl group or may have a heteroaromatic ring and a cycloalkyl group or a fused ring structure including a heterocyclic structure. In such an embodiment, Cy 11 is an aryl group or a heteroaromatic ring and a cycloalkyl L via either one of the groups or heterocyclic structures 10 -Cy 10 and L 11 -W 10 to may be concatenated, or alternatively, L 10 -Cy 10 and L 11 -W 10 One of the , Cy via an aryl group or heteroaromatic ring 11 is connected to L 10 -Cy 10 and L 1 1 -W 10 The other is a cycloalkyl group or a heterocyclic structure. 11 is linked 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: JPEG0007799657000022.jpg66170 where Cy 10 may be the left or right ring in the above diagram, i.e. the diagram is not where L 11 -W 10 is connected to either the left or right ring and both rings may be substituted.

[0123] In some embodiments, the compound of formula II is Cy 10 -L 10 -Cy 11 As follows It may have a core structure. JPEG0007799657000023.jpg68170 where Cy 10 may be the left or right ring in the above diagram, i.e., the diagram is Without limitation, where L 11 -W 10 can be connected to either the left or right ring. Optionally, both rings may be substituted.

[0124] In some embodiments, Cy in Formula II 10 and Cy 11 All are aryl or hetero In some embodiments, the compound of formula II has formula II-1. JPEG0007799657000024.jpg2381, During the ceremony, Ar 10 and Ar 11 each independently represents an optionally substituted C 6-10 Aromatic ring or In some embodiments, in Formula II-1, Ar 10 and Ar 11 are each independently an optionally substituted benzene ring or a substituted In some embodiments, A in Formula II-1 is a 5- or 6-membered heteroaromatic ring. r 10 and Ar 11 each independently represents an optionally substituted benzene ring, a thiophene ring, an optionally substituted furan ring, an optionally substituted pyridine ring, or a substituted In some embodiments, Ar in Formula II-1 is a pyrimidine ring that may be present. 10 and Ar 11 one of which is a bicyclic aryl group or a bicyclic heteroaromatic ring, each of which may be substituted; For example, in some embodiments, Ar 11 is an optionally substituted bicyclic aryl group Or it may be a bicyclic heteroaromatic ring.

[0125] In some embodiments, Cy in Formula II 11 is a benzene ring. In the formula II compound has the formula II-2. JPEG0007799657000025.jpg4160, During the ceremony, Ar 10 , L 10 , L 11 and W 10 is defined herein, see for example formula II-1 death, m is 0, 1, 2 or 3; R 20 Each occurrence of represents independently a halogen, -L 11’ -W 10’ , may be replaced I C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 cycloalkoxy group, optionally substituted an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 a 1-membered heterocyclic group, or two adjacent R 20 , or one R 20 and L 10 or L 11 represents an optionally substituted cycloalkyl group, a heterocyclic group, and the atom to which they are attached. , forming an aryl group or a heteroaromatic ring, where -L 11’ -W 10’ is chosen independently each time it appears, Here, L 11’ may be independently replaced by an empty C 1-6 Alkylene group, optionally substituted C 1-6 Heteroalkylene group, optionally substituted C 2-6 Arkeny C 2-6 Alkynylene group, optionally substituted C 3-6 Cycloa an alkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted 4- to 7-membered heterocyclylene group, and W 10’ appears every time , independently, -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3cR 4c ;-OSO 2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or JPEG0007799657000026.jpg1818, where 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 is defined herein, see for example Formula II, wherein the structural unit -L 11’ -W 10’ and -L 11 -W 10 Each instance of is independently chosen and identical may be the same or different.

[0126] In some embodiments, Cy in Formula II 11 is a benzo-fused ring. In one embodiment, the compound of formula II has formula II-3. JPEG0007799657000027.jpg3460, During the ceremony, Ar 10 , L 10 , L 11 and W 10 is defined herein, see for example formula II-1 death, m is 0, 1, 2 or 3; R 20 Each occurrence of represents independently a halogen, -L 11’ -W 10’ , may be replaced I C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 cycloalkoxy group, optionally substituted an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 a 1-membered heterocyclic group, or two adjacent R 20 , or one R 20 and L 10 or L 11 represents an optionally substituted cycloalkyl group, a heterocyclic group, and the atom to which they are attached. , forming an aryl group or a heteroaromatic ring, Here, L 11’ and W 10’ is defined herein, see for example Formula II-2, and , -L 11’ -W 10’ is chosen independently each time it appears, and Ring B is a 4- to 7-membered cycloalkyl ring, a 4- to 7-membered heterocyclic ring, a benzene ring, a 5- or 6-membered heteroaromatic ring, rings, each of which may be substituted.

[0127] In some embodiments, Cy in Formula II 11 is a benzo-fused bicyclic aryl or heteroaromatic group For example, in some embodiments, Cy in Formula II is 11 The following core structure It may have. JPEG0007799657000028.jpg64147, During the ceremony, L 10 -Cy 10 and L 11 -W 10 are independently connected via one of the two rings. Cy 11 The benzene ring may be connected to 1-3 R 20 Based on For example, with respect to the benzothiophene ring, in some embodiments Well, L 10 -Cy 10 may be attached to the thiophene ring, and L 11 -W 10 is benzene may be connected to a ring or vice versa, and in some cases, L 10 -Cy 10 and L 11 -W 10 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: JPEG0007799657000029.jpg84170In formula, Cy 10 , L 10 , R 20 , m, R 21 ,n,R 100a , L 11 and W 10 is determined by the original vow See, for example, formula II and subformulas, such as formula II-3, of the present application. In embodiments, Cy 10 is defined for formula II-3 10 is.

[0129] In some embodiments, the compound of formula II-3 may have formula II-4. JPEG0007799657000030.jpg3570, During the ceremony, Ar 10 , L10 , R 20 , m, L 11 and W 10 is defined herein, for example, in the formula I See I-3, n is 0 or 1, R 21 Each occurrence independently represents a halogen, oxo, -L 11’ -W 10’ , replaced C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl groups, optionally substituted Good C 2-6 Alkynyl group, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cycloalkoxy groups, substituted an optionally substituted phenyl group; an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted a 4- to 7-membered heterocyclic group, wherein L 11’ and W 10’ is defined in this application, e.g. See, for example, Formula II-2, and -L 11’ -W 10’ is chosen independently each time it appears. R, If valence allows, X 10 and X 11 are independently empty, -O-, -C(O )-, -S-, -NR 100a -, -S(O)-, -SO2- or -CR 101a R 10 2a - and where R 100a is the lone pair (if applicable), hydrogen, COR 2c , -SO2R 5 c , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or a substituted or R 100a is R 20 or R 21 Groups and Substitutions forming a heterocyclic or heteroaromatic ring which may be R 101a and R 102a are, if present, each independently hydrogen, -OH, halogen, optionally substituted C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, C may be replaced 1-6 Alkoxy group, optionally substituted C 3-6 cycloalkoxy groups, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered a heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group, or R 101a and R 102a together with the atoms to which they are attached, form an optionally substituted 3- to 7-membered cycloalkane. R 101a and R 102a On the other hand, R 20 or R 21 together with the group, an optionally substituted cycloalkyl group or heterocyclyl ring and R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl groups, C which may be substituted 2-6Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, substituted C 3-6 cycloalkoxy groups, optionally substituted phenyl groups; optionally substituted an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4- to 7-membered heterocyclic group; or R 20 or R 21 and L 10 , X 10 or X 11 and the atoms to which they are bonded. In addition, the cycloalkyl group, heterocyclic group, aryl group or heteroaromatic ring may be substituted. Complete. X 10 or X 11 If forms a double bond with one of the ring carbons, this is R 101a and R 102a CR where all 101a R 102a This is because the carbon valence is 4 In such a case, R 101a and R 102a One of them does not exist And X 10 or X 11 is the CR defined in this application. 101a or CR 102a is. X 10 or X 11 forms a double bond with one of the ring carbons, this is NR 100a Yes It is okay, here R 100a is usually a lone pair.

[0130] In some embodiments, the compound of formula II has formula II-5. JPEG0007799657000031.jpg3767, During the ceremony, Ar 10 , L 10 , R 20 , m, R 21 , n, L 11 and W 10 is defined in this application , see for example Formula II-4. Cy in Formula II (e.g., any of the subformulas described above in the present application, e.g., Formulas II-1 to II-4) 10 and Cy 11 may be linked directly or via multiple groups. In this embodiment, L in Formula II (e.g., Formulas II-1 to II-5) 10 is empty, -C(O )-, optionally substituted C 1-4 Alkylene group, optionally substituted C 2-4 Alkenylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted 4- to 7-membered heterocyclic group a crylene group, an optionally substituted phenylene group, an optionally substituted 5- or 6-membered heteroaryl group, olefin groups, -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 where: X 1 , X 2 and X 2a may be independently substituted C 1-4 Alkylene groups, substituted Good C 2-4 Alkenylene group, optionally substituted C 3-6 Cycloalkylene group, substituted an optionally substituted 4- to 7-membered heterocyclylene group, an optionally substituted phenylene group, a substituted Optional 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 may be independently substituted C 1-4 Alkylene groups, optionally substituted C 2-4 Alkenylene group, optionally substituted C 3-6 Cycloalkylene groups, optionally substituted a 4- to 7-membered heterocyclylene group, an optionally substituted phenylene group, an optionally substituted 5-membered or a 6-membered heteroarylene group, —C(O)—, —NR 100a -, -S(O)-, -SO 2- or -CR 101a R 102a - and Preferably, in some embodiments, -X 1 -G 1 -or-X 2 -G 2 -X 2a -O does not contain -N, -SS, -SN (except for SO2-N bonds) or -C(O)-S bonds; X 12 , X 13 and X 13a may be independently substituted C 1-4 Alkylene group, C may be replaced 2-4 Alkenylene group, optionally substituted C 3-6 cycloalkylene group , an optionally substituted 4- to 7-membered heterocyclylene group, an optionally substituted phenylene group, a substituted a 5- or 6-membered heteroarylene group, —O—, —C(O)—, —S—, —NR 1 00a -, -S(O)-, -SO2- or -CR 101a R102a - and and G 10 and G 11 independently, -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 1 3a - is OO, ON, SS, SN (excluding SO2-N bond), or -C(O)- Does not contain an S bond or three (or more) consecutive heteroatoms, where O—SO2— Except for O, O-SO2-N and N-SO2-N R 100 and R 100a are independently a lone pair (if applicable), hydrogen, or C OR 2c , -SO2R 5c , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3- 6-cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered hetero may be an aryl group or an optionally substituted 4- to 7-membered heterocyclic group; R 101 , R 101a , R 102 and R 102a are each independently hydrogen, -OH, Halogen; optionally substituted C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkoxy a substituted or unsubstituted phenyl group, an optionally ... is a 6-membered heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group, or R 1 01 and R 102 , or R 101a and R 102a along with the atoms to which they are bonded, It forms an optionally substituted 3- to 7-membered cycloalkyl or heterocyclyl ring.

[0131] In some embodiments, L in Formula II 10 may be empty and Cy 10 Cy 11 In some embodiments, L in Formula II is directly linked to 10 is empty, -O-, - C(O)-, -S-, -NR 100 -, -S(O)-, -SO2- or -CR 101 R 1 02 In some embodiments, L in Formula II may be 10 -X 1 -G 1 -also -X 2 -G 2 -X 2a - may be, where X 1 , X 2 and X 2a is independently , -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO2- or - CR 101a R 102a - and G 1 and G 2 are independently -C(O)-, - NR 100a-, -S(O)-, -SO2- or -CR 101a R 102a -It is.

[0132] In some embodiments, L in Formula II 10 -X 12 -G 10 - It may be. In some embodiments, X 12 may be replaced by C 2-4 Alkenylene groups, preferably JPEG0007799657000032.jpg1241 and G 10 -X 1 -G 1 -or-X 2 -G 2 -X 2a - where X 1 , X 2 and X 2a are independently -O-, -C(O)-, -S-, and -NR 100a -, -S(O)-, -SO2- or -CR 101a R 102a - and G 1 and G 2 are independently -C(O)-, -NR 100a -, -S(O)-, -SO2- or -CR 1 01a R 102a -It is. In some preferred embodiments, L in Formula II 10 teeth JPEG0007799657000033.jpg1241JPEG0007799657000034.jpg2251or It could also be JPEG0007799657000035.jpg1829.

[0133] In some embodiments, compounds of formula II may have the following core structure: JPEG0007799657000036.jpg158126In formula, L11 -W 10 may be directly connected to any one ring, and preferably two benzene rings or to a single benzene ring, where each ring is or multiple suitable substituents as described herein, e.g., each substituent may be F ;Cl;-OH;-NH2;-SO2NH2;-SO2NH(C 1-4 alkyl);-S O2NH(C 1-4 alkanoyl);-COOH; JPEG0007799657000037.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 group, C 1-4 Alkoxy groups, -OH, -NH2, and and fluorine, 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Independent of alkoxy groups, -OH, -NH2, and fluorine C optionally substituted with 1 to 3 substituents selected from 2-6 Alkenyl group; C 1-4 Al kill group, C 1-4 one independently selected from an alkoxy group, —OH, —NH2, and fluorine; C optionally substituted with 3 substituents 2-6 Alkynyl group; C 1-4 Alkyl groups and C optionally substituted with 1 to 3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4 substituted with 1 to 3 substituents independently selected from alkyl groups and fluorine; Good C 3-6 a cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH2, and fluorine. Good C 1-4 Alkoxy group; optionally substituted C 3-6 Cycloalkyl groups; optionally substituted a 4- to 10-membered heterocyclic group; an optionally substituted 5- to 10-membered heteroaryl group; or a substituted Good C 6-10 The aryl groups may be independently selected from the group consisting of aryl groups. In this state, L 11 -W 10 is NH2 or NH(C 1-4 alkanoyl) and two benzoates It is connected to one of the benzene rings, or to only one benzene ring, and the other ring is methyl. It may be substituted with one or two substituents selected from an alkyl group and a methoxy group. In some particular embodiments, the compound of formula II has a formula according to formula II-6 or II-7. do. JPEG0007799657000038.jpg36151, During the ceremony, L 11 , W 10 , R 20 and m is defined herein, see for example Formula II-3: p is 0, 1, 2, 3 or 4; R 22 Each occurrence of represents independently a halogen, -L 11’ -W 10’ , may be replaced I C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 cycloalkoxy group, optionally substituted an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 a 1-membered heterocyclic group, or two adjacent R 22 along with the atoms to which they are bonded, forming an optionally substituted cycloalkyl group, heterocyclic group, aryl group or heteroaromatic ring, where L 11’ and W 10’ is defined herein, see for example Formula II-2, and -L 11’ -W 10’ is chosen independently each time it appears. L in Formula II (e.g., any subformula, e.g., Formulas II-1 to II-7) 11 is usually empty Yes, if applicable, W 10 The base is Cy 11 In some embodiments, is L in formula II 11 is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Al quinylene group or C 1-4 It may also be a heteroalkylene group. For example, W 10 The base is Methylene Cy via the phenyl or ethenyl group 11 may be connected to Multiple types of W 10 The group is applicable to compounds of formula II (e.g., formulas II-1 to II-7). In a preferred embodiment, W 10 The groups, each occurrence, independently represent -OH, -NH, -SO 2NH2, -SO2NH(C 1-4 alkyl);-SO2NH(C 1-4 alkanoyl) , -COOH, JPEG0007799657000039.jpg1818, -C(O)(OC 1-10alkyl), -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), where each C 1-4 Alkyl group independently, C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2, and In some embodiments, the alkyl group may be substituted with 1 to 3 substituents independently selected from fluorine. In the form of W in formula II 10 The groups are -OH, -OMe, -NH2, -SO2NH2, and -SO 2NH(acetyl), -COOH, JPEG0007799657000040.jpg1818 or -OC(O)-CH3. As described herein, L 11’ -W 10’ In some embodiments, Cy 10 or C y 11 For example, Ar 10 or Ar 11 In some cases, the substituents may be selected as the substituents used in the In this case, L in formula II (including any of the subformulas described above in the present application, for example, formulas II-1 to II-7) 1 1’ appears, e.g., Ar 10 or Ar 11 With respect to (where applicable), independent It may be empty, i.e., W 10’ The base is Cy 10 or Cy 11 It may be connected directly to K or C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 an alkynylene group or C 1-4 Heteroalkylene groups. For example, W10’ The group can be, for example, Ar 10 or Ar 1 1 For (where applicable), Cy 10 or Cy 1 1 Where applicable, the formula II (any of the subformulas hereinbefore, e.g., the formula W in (including II-1 to II-7) 10’ Each occurrence of represents independently -OH, -NH 2 , -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 Al Kanoyl), -COOH, JPEG0007799657000041.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), where each C 1-4 a The alkyl groups are independently C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2 and fluorine. In some embodiments, when applicable, W in Formula II 10’ Each instance of is -OH, - OMe, -NH2, -SO2NH2, -SO2NH(acetyl), -COOH or -O- It may also be C(O)-CH3. The multiple groups may be any of the groups of formula II (e.g., formulas II-1 to II-7, if applicable). R in 20 , R 21 and R22 In some embodiments, R 20 , R 21 and R 22 Each occurrence of each of the following is independently: F; Cl; -OH; -NH2 ;-SO2NH2;-SO2NH(C 1-4 alkyl);-SO2NH(C 1-4 Arca Noyl);-COOH; JPEG0007799657000042.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 group, C 1-4 Alkoxy groups, -OH, -NH2, and and fluorine, 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Independent of alkoxy groups, -OH, -NH2, and fluorine C optionally substituted with 1 to 3 substituents selected from 2-6 Alkenyl group; C 1-4 Al kill group, C 1-4 one independently selected from an alkoxy group, —OH, —NH2, and fluorine; C optionally substituted with 3 substituents 2-6 Alkynyl group; C 1-4 Alkyl groups and C optionally substituted with 1 to 3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4 substituted with 1 to 3 substituents independently selected from alkyl groups and fluorine; Good C 3-6 a cycloalkoxy group; or C 1-4 Alkyl group, C1-4 alkoxy group , -OH, -NH2, and fluorine. Good C 1-4 In some embodiments, R 20 , R 21 Reach BiR 22 each occurrence of may independently be: F; Cl; -OH; -NH2; -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 Arcano yl), -COOH; JPEG0007799657000043.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 alkenyl);C1 -4 Alkyl group, C 1-6 independently selected from an alkoxy group, -OH, -NH2, and fluorine; C optionally substituted with 1-3 substituents 1-6 alkyl group; or C 1-4 Alkyl group, C 1-6 1 to 3 independently selected from an alkoxy group, —OH, —NH2, and fluorine C optionally substituted with 2-6 In some embodiments, the group may be an alkenyl group. In this state, R 20 , R 21 and R 22 Each occurrence of , C 1-4 Alkyl group, C 2-6 Alkenyl group or -O-(C 1-4alkyl) In some embodiments, R 20 , R 21 and R 22 Each of the each occurrence independently represents -OH, -OMe or JPEG0007799657000044.jpg1622. In some embodiments, R 20 One or more instances of R 2 1 One or more instances of and / or R 22 One or more instances of L as described herein 11’ -W 10’ may be. Typically, m and p are 0, 1, 2 or 3, preferably 1 or 2, where applicable. Typically, n is 0, 1 or 2, preferably 0 or 1, where applicable.

[0134] In some embodiments, the compound of formula II is any of formulas II-8 through II-10. It may have a formula by one. JPEG0007799657000045.jpg3569, JPEG0007799657000046.jpg3766 or JPEG0007799657000047.jpg3368, During the ceremony, R 20 , R 22 , m, and p are defined herein. In some embodiments, m is 1 or is 2 and p is 1, 2, or 3. In some embodiments, R 20 and R 22 brain Each of these, each time it occurs, is independently: F; Cl; -OH; -NH2; -SO2NH 2. -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 alkanoyl), -C OOH; JPEG0007799657000048.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 alkenyl);C1 -4 Alkyl group, C 1-6 independently selected from an alkoxy group, -OH, -NH2, and fluorine; C optionally substituted with 1-3 substituents 1-6 alkyl group; or C 1-4 Alkyl group, C 1-6 1 to 3 independently selected from an alkoxy group, —OH, —NH2, and fluorine C optionally substituted with 2-6 It is an alkenyl group.

[0135] In some embodiments, any applicable structural unit in Formula II JPEG0007799657000049.jpg2132 may be chosen from the following: JPEG0007799657000050.jpg87104 In some particular embodiments, the compound of formula II is JPEG0007799657000051.jpg3167, JPEG0007799657000052.jpg4267, JPEG0007799657000053.jpg3561 or JPEG0007799657000054.jpg3561, Or it may be a pharmaceutically acceptable salt or ester.

[0136] In some embodiments, the compounds of the present application have Formula III or are pharmaceutically acceptable. The compound may be characterized as a salt or an ester. JPEG0007799657000055.jpg1942, During the ceremony, Ar 20 is an optionally substituted aromatic ring (e.g., C 6-10 aromatic ring) or optionally substituted a heteroaromatic ring (e.g., a 5- to 10-membered heteroaromatic ring), L 20 is empty, may be replaced C 1-6 Alkylene group, optionally substituted C 1-6 Haitai an optionally substituted C alkylene group; 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted aryl an optionally substituted heteroarylene group, an optionally substituted heteroarylene group, or an optionally substituted 4- to 7-membered heteroarylene group; is a crylene group, W 20 -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2 NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or JPEG0007799657000056.jpg1818, where: R 1 and R 1aare each independently hydrogen, an optionally substituted alkyl group, a substituted an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted is a good heterocyclic group, R 3 and R 4 are each independently hydrogen, -COR 2b , -SO2R 5b , replaced by Good C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl groups, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted a phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- a 7-membered heterocyclic group, or R 3 and R 4 are substituted together with the atoms to which they are attached. forming a 4- to 7-membered heterocyclic group which may be R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 a Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco oxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cyclo an alkoxy 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, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C3 -6 a cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5- or 6-membered phenyl group; or an optionally substituted 4- to 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 teeth together with the atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclic group.

[0137] In some embodiments, Ar in Formula III 20 is an optionally substituted benzene ring or For example, in some embodiments, the compound of Formula II is a 5- or 6-membered heteroaromatic ring. Ar in I 20 The ring may be an optionally substituted benzene ring, an optionally substituted thiophene ring, or a substituted an optionally substituted furan ring, an optionally substituted pyridine ring, or an optionally substituted pyrimidine ring; In some embodiments, Ar in Formula III 20 may be substituted The aromatic ring may be a bicyclic aryl group or a bicyclic heteroaromatic ring, each of which may be substituted. In such an embodiment, L 20 -W 20 may be connected to any one of the two rings .

[0138] In some embodiments, Ar in Formula III 20 is an optionally substituted benzene ring where two adjacent substituents, together with the carbon to which they are attached, are substituted. The alkyl group may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaromatic ring. For example, in some embodiments, Ar in Formula III 20 is a benzo-fused bicyclic aryl group or For example, in some embodiments, Ar in Formula III may be a heteroaromatic ring. 2 0 may have the following structure: JPEG0007799657000057.jpg64147, During the ceremony, -L 20 -W 20 may be connected to either one of the two rings, where either One or both rings may be substituted.

[0139] In some embodiments, the compound of formula III has formula III-1, III-2, or III-3 may have JPEG0007799657000058.jpg68112In formula, L 20 and W 20 is defined herein, m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3; R30 and R 31 Each occurrence of -L 20’ -W 20’ , may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Arkeny optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 alkoxy group , may be replaced by C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cycloalco an oxy 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, wherein -L 20’ -W 20’ appears are chosen independently each time, where L 20’ is replaced independently with an empty string each time it appears. Good C 1-6 Alkylene group, optionally substituted C 1-6 Heteroalkylene groups, substituted C 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene groups, substituted C 3-6 a cycloalkylene group, an optionally substituted arylene group, an optionally substituted a heteroarylene group or an optionally substituted 4- to 7-membered heterocyclylene group, and , W 20’ Each time it appears, it is used independently: -OR 1 ;-COR 2 ;-COOR 1a ;-O COOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2NR3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a ;-OSO2R 5a or JPEG0007799657000059.jpg1818, where R 1 , R 1a , R 2 , R 2a , R 2b , R 3 , R 4 , R 3a , R 3 b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 5a and R 5b is defined herein, see for example Formula III: Ring B is a 4- to 7-membered cycloalkyl ring, a 4- to 7-membered heterocyclic ring, a benzene ring, a 5- or 6-membered heteroaromatic ring, rings, each of which is independently selected from 1 to 3 R 31 is replaced by Also, If valence allows, X 20 and X 21 are independently empty, -O-, -C(O )-, -S-, -NR 100a -, -S(O)-, -SO2- or -CR 101a R 10 2a - and where R 100a is the lone pair (if applicable), hydrogen, COR 2c , -SO2R 5 c, may be replaced by C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or a substituted or R 100a and R 30 or R 31 One of the together with the atoms to which they are attached, may be substituted heterocyclic or heteroaromatic rings, e.g., an optionally substituted 5- or 6-membered heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group; Accomplished, R 101a and R 102a are, if present, each independently hydrogen, -OH, halogen, optionally substituted C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, C may be replaced 1-6 Alkoxy group, optionally substituted C 3-6 cycloalkoxy groups, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered a heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group, or R 101a and R 102a together with the atoms to which they are attached, form an optionally substituted 3- to 7-membered cycloalkane. R 101a and R 102a On the other hand, R 30 or R 31together with the group, an optionally substituted cycloalkyl group or heterocyclyl ring Forming R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl groups, C which may be substituted 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, substituted C 3-6 cycloalkoxy groups, optionally substituted phenyl groups; optionally substituted an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4- to 7-membered heterocyclic group; Or two adjacent R 30 or two adjacent R 31 , or R 30 or R 31 Reach and X 20 or X 21 together with the atom to which they are attached represent an optionally substituted cycloalkyl group. The aryl group forms a heterocyclic group, a heterocyclic group, an aryl group, or a heteroaromatic ring. X 20 or X 21 If forms a double bond with one of the ring carbons, this is R 101a and R 1 02a CR where all 101a R 102a This is because the carbon valence is 4. In this case, R 101a and R 102a One of them does not exist , and X 20 or X 21 is the CR defined in this application. 101a or CR 102a X 20 or X 21forms a double bond with one of the ring carbons, this is NR 100a And Well, here R 100a is usually a lone pair. In addition, the structural unit -L 20’ -W 20’ and -L 20 -W 20 Each instance of are selected and may be the same or different.

[0140] In some embodiments, the compound of formula III may have any of the following structures: JPEG0007799657000060.jpg197170In formula, R 30 , m, R 31 ,n,R 100a , L 20 and W 20 is defined in this application, e.g. See, for example, formula III and subformulas, such as formulas III-1 to III-3, herein, wherein the tricyclic structure For this structure, the piperidine ring or morpholine ring may be substituted. L in Formula III (e.g., any subformula, e.g., Formulas III-1 to III-3) 20 is usually , is empty, i.e., W 20 The group is Ar 20 In some embodiments, the formula L in III 20 is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkini cyclohexane or C 1-4 It may also be a heteroalkylene group. For example, W 20 The group is a methylene group or Ar via the ethenyl group 20 may be connected to Multiple types of W 20 The group may be of formula III (e.g., any subformula, such as formulas III-1 to III-3): In a preferred embodiment, W in formula III 20 -OH, -CO OH, JPEG0007799657000061.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 alkyl), So, each C 1-4 The alkyl groups are independently C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH2, and fluorine; In some embodiments, the compound of formula III (e.g., any subformula, e.g., formula III) may be used. -1~III-3) 20 The groups are -OH, -NH2, -SO2NH2, -SO2NH (acetyl), JPEG0007799657000062.jpg1818, -C(O)-(O-C8 alkyl), -COOH or -OC(O)-CH3. As described herein, L 20’ -W 20’ In some embodiments, Ar 20 Used for Where applicable, the substituents of formula III (any of the above subgroups of this application) may be selected as L in the formula (including, for example, formulas III-1 to III-3) 20’ independently each time it appears. May be empty, i.e., if applicable, W 20’ The group is Ar 20 , or C1-4 Alkire group, C 2-4 Alkenylene group, C 2-4 Alkynylene group or C 1-4 Heteroalkylene For example, where applicable, W 20’ The group is a methylene group or an ethene group. Ar via the aryl group 20 Where applicable, Formula III (as defined above in this application) may be connected to W in any of the sub-formulas, including formulas III-1 to III-3 20’ appears every time , independently, -OH, -COOH, JPEG0007799657000063.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 alkyl), So, each C 1-4 The alkyl groups are independently C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH2, and fluorine; In some embodiments, when applicable, W in Formula III 20’ Each instance Tansu is -OH, -NH2, -SO2NH2, -SO2NH(acetyl), JPEG0007799657000064.jpg1818, -COOH, -C(O)(O-C8 alkyl) or -OC(O)-CH3 good. The multiple groups may be any applicable group of Formula III (e.g., any sub-formula, e.g., Formulas III-1 to III-I). II-3) in R 30 and R 31 In some embodiments, R 30 and R 31 Each of the following, each occurrence, independently represents: F; Cl; -OH; -COOH; - OC(O)NH2;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C1 -4 alkyl);C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2, and C optionally substituted with 1 to 3 substituents independently selected from fluorine 1-4 alkyl groups; C 1-4 Alkyl group, C 1-4 Independently of the alkoxy group, -OH, -NH2, and fluorine C optionally substituted with 1 to 3 substituents selected from 2-6 Alkenyl group; C 1-4 Archi group, C 1-4 1- independently selected from an alkoxy group, —OH, —NH2, and fluorine; C optionally substituted with 3 substituents 2-6 Alkynyl group; C 1-4 Alkyl groups and fluorine C optionally substituted with 1 to 3 substituents independently selected from 3-6 cycloalkyl group ;C 1-4 substituted with 1 to 3 substituents independently selected from alkyl groups and fluorine; Good C 3-6 a cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy groups, may be substituted with 1 to 3 substituents independently selected from -OH, -NH2, and fluorine; I C 1-4 In some embodiments, R30 and R 31 of Each of them, independently, is -OH, C 2-6 Alkenyl group, -O-( C 1-4 alkyl), -COOH or -C(O)(OC 1-10 Even if it is alkyl In some embodiments, R 30 and R 31 Each of these, as it appears, In some embodiments, R 30 One or more of Instance and / or R 31 One or more instances of may be independently selected. L as described in 20’ -W 20’ It may be. Typically, m is 0, 1, 2 or 3, preferably 2 or 3. Typically, n is 1, 2 or 3. do.

[0141] In some embodiments, the present disclosure provides a compound JPEG0007799657000065.jpg3178, or a pharmaceutically acceptable salt or ester thereof.

[0142] In some embodiments, the present disclosure provides a compound JPEG0007799657000066.jpg3164, or a pharmaceutically acceptable salt or ester thereof, wherein q is 1, 2, 3, 4, or or 5, and Glu is a glucose residue. Disclosure is JPEG0007799657000067.jpg6573, a pharmaceutically acceptable salt or ester thereof is further provided.

[0143] In some embodiments, the compounds of the present application may be alkaloids with antibacterial activity. As shown herein, some indole alkaloids, such as vinca alkaloids, tabazoline alkaloids, Vincin, vindoline, vinblastine, vincristine, etc. are produced by, for example, Bacillus megaterium In some embodiments, the compounds of the present application can effectively kill microorganisms such as bacteria. The compounds are characterized by formula IV-1 or IV-2, and are tabasonine or vindoline and derivatives . JPEG0007799657000068.jpg51123, During the ceremony, R 40 is hydrogen; -COR 2 ;-COOR 1a ;-SO2R 5a Optionally substituted arsenic alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted optionally substituted cycloalkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups a group or an optionally substituted heterocyclic group, R 41 -OR 1 ;-OCOOR 1a ;-OCONR 3b R 4b ;-OCOR 2a ;also Ha-OSO2R 5a and n is 0 or 1; R 42 , R 43 and R 44 are each independently hydrogen, -OR 1 ,OCOR 2a or -OSO2R 5a and L 30 is empty or a methylene group, W 30 -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-OSO2NR 3d R 4d ;-OCO R 2a ;or -OSO2R 5a and where: R 1 and R 1a are each independently hydrogen, an optionally substituted alkyl group, a substituted an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted is a good heterocyclic group, R 3 and R 4 are each independently hydrogen, -COR 2b , -SO2R 5b , replaced by Good C 1-6 alkyl group, optionally substituted C 2-6 Alkenyl groups, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted a phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4- a 7-membered heterocyclic group, or R 3 and R 4 are substituted together with the atoms to which they are attached. forming a 4- to 7-membered heterocyclic group which may be R 2 , R 2a , R 2b , R 5 , R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , may be replaced by C 1-6 alkyl group, optionally substituted C2-6 a Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco oxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 3-6 Cyclo an alkoxy 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, and R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 4c , R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C3 -6 a cycloalkoxy group, an optionally substituted phenyl group; an optionally substituted 5- or 6-membered phenyl group; or an optionally substituted 4- to 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 teeth together with the atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclic group.

[0144] In some embodiments, the compound of formula IV-1 or IV-2 has the formula IV-3 to IV-6 It may have a formula by one. JPEG0007799657000069.jpg81163JPEG0007799657000070.jpg77109or JPEG0007799657000071.jpg7483In formula, R 45 is hydrogen or a methyl group.

[0145] In some embodiments, R of any one of formulas IV-1 to IV-6 40 is hydrogen , C 1-4 Alkyl group or C 1-4 It may also be an alkanoyl group. L in Formulas IV-1 to IV-6 30 is normally empty. However, in some embodiments represents L in formulas IV-1 to IV-6. 30 may be CH2. W in formulas IV-1 to IV-6 30 Generally, the carbohydrates that can be used in the compositions and methods of the present application are The naturally occurring indole alcohols are carboxylic acid derivatives, amine derivatives, or alcohol derivatives. The kaloid tabasonine has a CO2Me group 30 Including L 30 is empty. CO2Me The groups may be converted to the corresponding acids, amides, etc. via conventional transformations, or may be rearranged, e.g., by a C1C reaction. It can be reduced or converted to an amine via a Curtius rearrangement. In this embodiment, W in formulas IV-1 to IV-6 30 are -OH, -NH2, -OSO2NH2, - COOH, -C(O)(OC 1-10 alkyl), -C(O)(OC 2-10 Arke nyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO )-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 The alkyl groups are independently C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, may be substituted by 1 to 3 substituents independently selected from -NH2 and fluorine; In some embodiments, W in Formulas IV-1 to IV-6 30 -OH, -NH2, -O SO2NH2, -C(O)-(O-C8 alkyl), -COOH or -OC(O)NH2 may be. In some particular embodiments, the compound may have the following structure: JPEG0007799657000072.jpg3895.

[0146] In some embodiments, the compounds of the present application are glycosides or pharmaceutically active compounds with antibacterial activity. As shown in the present application, some examples of glycosides may be For example, ginsenosides and gallic acid glycosides are produced by bacteria such as Bacillus megaterium. Other useful glycosides have demonstrated antibacterial activity in the field. The glycosides may include any one of these glycosides known to have, for example, The corresponding aglycones of the compounds are phenolic compounds, flavonoids, coumarins, benzoic acids or sulfuric acid. Glycosides include glycosides characterized as steroids. However, other glycosides may be used. In some embodiments, the glycoside is an amphiphilic may be characterized as being antimicrobial, thereby disrupting biofilms and enhancing the antimicrobial activity of glycosides. In some embodiments, glycosides can be characterized as saponins. may be attached, which can act as a "surfactant" and contribute to the killing of bacteria. It may contain glycosides derived from multiple types of plants.

[0147] In some embodiments, the glycosides of the present application may be characterized by formula V: JPEG0007799657000073.jpg4472In formula, Each R 50 are independently hydrogen, -L 50 -D, an oxygen protecting group or a sugar residue; L 50 is empty or -C(O)-, D is an optionally substituted aryl group (e.g., C 6-10 aryl group), optionally substituted heteroaryl groups (e.g., 5- to 14-membered heteroaryl groups), aryl groups, heteroaryl groups, a substituted alkyl group containing two or more rings independently selected from a methyl group, a cycloalkyl group, and a heterocyclic group; fused rings (e.g., 8-14 membered, e.g., benzo-fused cycloalkyl groups / heterocycles) which may be a pyrido-fused cycloalkyl / heterocyclic group) or a steroid residue having the formula VA. the law of nature, JPEG0007799657000074.jpg4267 where, if valence allows, JPEG0007799657000075.jpg826 is a steroid skeleton or any R 51 may be linked to formula VA via a group, where R 51 Each occurrence of represents independently an optionally substituted alkyl group, an optionally substituted an optionally substituted alkenyl group, an optionally substituted alkynyl group, an -O optionally substituted oxygen protecting group; H, oxo, halogen, optionally substituted cycloalkyl group, optionally substituted alkoxy a cycloalkoxy group which may be substituted, an amino group which may be substituted, A phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group. Or two R 51 The groups, together with the atoms to which they are attached, are optionally substituted cycloalkyl groups. forming an alkyl group, a heterocyclic group, an aryl group or a heteroaromatic ring, m is an integer from 1 to 8, and where -L 50 -D is chosen independently each time it appears.

[0148] In some embodiments, each R 50 is hydrogen.

[0149] In some embodiments, 1 to 4 R 50 are independently chosen -L 50 -D Two or more -L 50 When the -D unit is linked to a pyranose unit in formula V, These are preferably the same. In some embodiments, one or more (e.g., one or more (2) R 50 is a sugar residue linked to the remainder of formula V via a glycosidic bond. In some embodiments, the sugar residue is a glucose residue or a rhamnose residue. . L in formula V 50 may be empty or a carbonyl group, i.e., -C(O)-, which is the linking group is a phenolic -OH from a benzoic acid or heteroaryl counterpart or a COOH group It depends on whether it is. Several types of residues are available as D, typically phenolic compounds, coumarins, and flavonoids. or a residue derived from a sterol, and in some embodiments, without a glycosidic unit, It may have activity.

[0150] In some embodiments, D may be selected from the following optionally substituted rings: JPEG0007799657000076.jpg80123In formula, R 100a is a lone pair (if applicable), hydrogen, nitrogen protecting group, optionally substituted C1 -6 alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 a alkynyl group, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted phenyl groups , an optionally substituted 5- or 6-membered heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group or R 100a The heterocyclic ring or heterocyclic ring optionally substituted with a phenyl group or a pyridine ring (b) forming an aromatic ring, where: JPEG0007799657000077.jpg826 may be concatenated to D via any available position, and each ring system of D is optionally substituted with 1-5 (e.g., 1, 2, or 3) substituents; Each substituent is independently: -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;-SO2NH 2;-SO2NH(C 1-4 alkyl);-SO2NH(C 1-4 alkanoyl); halo Gen; optionally substituted C 1-6 Alkyl group; optionally substituted C 2-6 alkenyl groups; C which may be substituted 2-6 Alkynyl group; optionally substituted C 3-6 cycloalkyl groups; C which may be substituted 1-6 Alkoxy group; optionally substituted C 3-6cycloalkoxy group an optionally substituted amino group; an optionally substituted phenyl group; an optionally substituted 5 or 6 or an optionally substituted 4- to 7-membered heterocyclic group.

[0151] In some embodiments, each ring system of D as defined above is substituted with 1-5 substituents. each substituent may be independently selected from the group consisting 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 Al Kil);-NH2;-SO2NH2;-SO2NH(C 1-4 alkyl);-SO2NH (C 1-4 alkanoyl);C 1-4 1 to 3 substituents independently selected from alkyl groups may be substituted with C 1-4 Alkyl group; C 1-4 Alkoxy groups, -OH, -NH2, and and fluorine;C 1-4 Alkyl group, C 1-4 Alkoxy groups, -OH, -NH2, and fluorine C optionally substituted with 1 to 3 substituents independently selected from 2-6 Alkenyl group; C1 -4 Alkyl group, C 1-4 independently selected from an alkoxy group, -OH, -NH2, and fluorine; C optionally substituted with 1-3 substituents 2-6 Alkynyl group; C 1-4 Alkyl group and C optionally substituted by 1 to 3 substituents independently selected from fluorine. 3-6 Cyclo Alkyl group; C 1-4alkyl groups, and 1 to 3 substituents independently selected from fluorine; C which may be substituted 3-6 a cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 Al substituted with 1 to 3 substituents independently selected from koxy, -OH, -NH2, and fluorine; C 1-4 The alkoxy group is selected from the group consisting of alkoxy groups.

[0152] In some embodiments, D may be selected from the following: JPEG0007799657000078.jpg210125, During the ceremony, Each phenolic OH group is linked to a sugar (e.g., glucose) via a glycosidic bond. Good too.

[0153] In some embodiments, D is derived from a sterol. For example, in some embodiments, So, D is JPEG0007799657000079.jpg4257, During the ceremony, R 52 is an optionally substituted alkyl group or an optionally substituted alkenyl group, where each remaining -OH group in D may be linked to a sugar via a glycosidic bond. good. Preferably, R 52 teeth It could also be JPEG0007799657000080.jpg1235. In any of the embodiments described above, the glycoside may have the formula V-1 or V-2. JPEG0007799657000081.jpg82104 or JPEG0007799657000082.jpg80127 In some embodiments, the glycoside may be a compound selected from the following: JPEG0007799657000083.jpg5360 and JPEG0007799657000084.jpg6655.

[0154] In some embodiments, the compounds of the present application are selected from the group consisting of benzoic acid, benzyl alcohol, coumarins, , catechols, polyphenols, chalconoids (including licochalcones), etc. Rubens such as resveratrol, isoresveratrol, etc., phenolic acids such as p- Hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanilla Phosphoric acid, syringic acid, cinnamic acid, coumaric acids, caffeic acids, ferulic acids, chlorogenic acid , sinapic acids, etc., flavonoids such as catechin, naringenin, quercetin, rutin , chrysin, etc., tannins such as ellagic acid, and pharmaceutically acceptable salts or esters thereof, The glycoside may be any one or more compounds selected from the glycosides.

[0155] In some embodiments, the compounds of the present application are compounds 1-8 or pharmaceutically acceptable salts or esters thereof. It may be any one or more of the following: JPEG0007799657000085.jpg40361, JPEG0007799657000086.jpg43392, JPEG0007799657000087.jpg33363, JPEG0007799657000088.jpg30544, JPEG0007799657000089.jpg28505, JPEG0007799657000090.jpg27616, JPEG0007799657000091.jpg55637, and JPEG0007799657000092.jpg62528

[0156] The compounds of the present application may usually be isolated from natural sources or, alternatively, may be prepared by conventional chemical synthesis. For example, each of Compounds 1 to 8 is available as a commercial product and has been identified as a component in plants. Unless otherwise indicated, in any of the embodiments of the present application, the compound may be derived from a synthetic source. Unless otherwise indicated, in any of the embodiments of the present application, the compound may be 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). Usually, such a separated compound is also substantially pure, for example, having a purity of 80%, 85%, 90%, 9 5% or more 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 is separated or purified before being mixed with other components of the composition, that is, it is in a separated or substantially pure form.

[0157] Synthetic chemical transformations and protecting group methods (protection and deprotection) available for the synthesis of the compounds to be applied are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, 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 d Sons (1995) and subsequent versions.

[0158] Pharmaceutical Composition In some embodiments, a pharmaceutical composition comprising one or more compounds of the present disclosure and optionally a pharmaceutically acceptable excipient is provided. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure and a drug. Pharmaceutically acceptable excipients include those known in the art. Non-limiting examples of suitable excipients include encapsulating materials or additives such as absorption enhancers, acid Antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants , emulsifiers, extenders, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, releasing agents, This includes sterilizing agents, sweeteners, solubilizing agents, humectants, and mixtures thereof. Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Will (Iams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference) discloses several types of excipients for preparing pharmaceutical compositions and known techniques for their preparation. It has been done.

[0159] The pharmaceutical composition may include any one or more compounds of the present disclosure. For example, some In embodiments, the pharmaceutical composition comprises a compound of Formula I, II, III, IV-1, IV-2, V, or any of these. A compound of any subformula, or any of compounds 1 to 8, or a pharmaceutically acceptable salt thereof, Unless otherwise indicated, in any of the above embodiments of the present application, the pharmaceutical composition may include a compound selected from Compounds 1 to 8 or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any of the foregoing embodiments of the present application, the pharmaceutical composition may comprise Compound 1. to 8, or a pharmaceutically acceptable salt or ester thereof, It may be possible to exclude it from the

[0160] Pharmaceutical compositions may contain varying amounts of the disclosed compounds, depending on a number of factors, such as the compound's anticipated use and efficacy. In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable excipient. In some embodiments, a therapeutically effective amount of a disclosed compound may be an amount that effectively treats AMD (e.g., wet AMD, dry AMD) as described herein, which may depend on the entity being treated, the stage and severity of the AMD, the composition of the compound, the time of administration, the route of administration, the duration of treatment, the compound's potency, its clearance, and whether another medication is administered concomitantly. In some embodiments, a therapeutically effective amount of a disclosed compound may be an amount that effectively kills or inhibits the growth of microorganisms, such as Bacillus megaterium, in a subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, e.g., in the gut. In some embodiments, a therapeutically effective amount of a compound of the present disclosure can be an amount that effectively kills or inhibits the growth of microorganisms, e.g., in the eye (e.g., intraocular space), blood, and / or gastrointestinal tract, e.g., the intestine, of a subject, such as, for example, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus pyogenes, FaeciumIn some embodiments, the therapeutically effective amount of a compound of the present disclosure can be an amount that effectively treats soft drusen symptoms, such as reducing soft drusenoid lesions.

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

[0162] The active ingredient, pharmaceutically acceptable excipient and / or any other component in said pharmaceutical composition of the present application The relative amounts of the components will depend on the identity, size and / or condition of the subject being treated, and further This will vary depending on the route of administration of the composition.

[0163] The pharmaceutical compositions of the present application may be formulated to be delivered via any known delivery route. The delivery route may include, but is not limited to, oral, injectable or infusible, topical, intraocular, inhalation, etc. Not restricted.

[0164] In some embodiments, the pharmaceutical composition may be prepared for oral administration. discrete units, e.g., capsules, pills, cachets, each containing a predetermined amount of active compound; , lozenges or tablets, powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or water It may also be present as an oil-in-oil or water-in-oil emulsion. Excipients for preparing compositions for oral administration Non-limiting examples of suitable excipients include agar, alginic acid, water, and the like. Aluminum oxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol cellulose, carbomer, castor oil, cellulose acetate, cocoa butter, corn starch Chi, corn oil, cottonseed oil, crospovidone, diglyceride, ethanol, ethyl cellulose , ethyl laurate, ethyl oleate, fatty acid ester, gelatin, germ oil, glucose glycerol, groundnut oil, hydroxypropyl methyl Cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, stearin Magnesium carbonate, malt, mannitol, monoglycerides, olive oil, peanut oil nut oil), potassium phosphate, potato starch, povidone, propylene glycol , Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate Thorium salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid , stearyl fumarate, sucrose, surfactant, talc, tragacanth, tetrahydrofurf The composition includes disodium EDTA, glycerin, glycerol ... triglyceride, water, and mixtures thereof.

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

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

[0167] The compounds of the present disclosure may be used as single treatments, in combination with each other, or For example, in some embodiments, the present invention may be used in combination therapy. The pharmaceutical composition may further comprise another antibiotic and / or anti-VEGF agent. In certain embodiments, such antibiotic and / or anti-VEGF agent are contained in a single dosage form. In some embodiments, commercially available (e.g., FDA approved) Any antibiotic and anti-VEGF agent (as defined above) may be used in combination with the compounds and compositions of the present application. In some embodiments, the antibiotic is a β-lactam antibiotic, an aminoglycoside, Lycoside antibiotics, tetracycline antibiotics, chloramphenicol antibiotics, Macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimides dazole antibiotics, rifamycin antibiotics, echinocandin antibiotics, polyenes antibiotics, pyrimidine antibiotics, allylamine antibiotics, or azole antibiotics or a combination thereof. For example, in some embodiments, the antibiotic is β-lactam antibiotics, such as penicillins (e.g., penicillin V), amoxicillin ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, Peracillin, pivampicillin, pivmecillinam, ticarcillin, cephalosporins, etc. Cefastril, cefadroxil, cephalexin, cephaloglycin, cephalon cephaloridine, cephalothin, cephapirin, cefatrizine, cefazaflur , cefazedone, cefazolin, cephradine, cefroxadine, ceftezole, cefa Chlor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin Chin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefzi Nil, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, Cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, cefti Ofur, ceftaroline, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime Jim, Cefclidin, Cefepime, Cefluprenum, Cefoselis, Cefozopran, Cefopram Fupirome, cefquinome, ceftobiprole, ceftaroline, cefaclomedine, cephalosporin Ram, cefaparole, cefcanel, cefedrol, cefenpidon, cefetrizole , cefibitril, cefmatilen, cefmepidium epidium), cefovecin, cefoxazole, cefrotil, cefsumide, cefra Thyme, ceftioxide, thienamycins, monobactams, β-lactamase inhibitors , methoxypenicillins; aminoglycoside antibiotics, such as streptomycin, amikacin, amiodarone, cyclosporine ... , neomycin (e.g., neomycin B, neomycin C, neomycin E), ribosomal Isin, micronomycin, azithromycin, dibekacin, sisomicin, netilmycin tetracycline antibiotics, such as tetracycline, paromomycin, and thiazolinone; Iclin, oxytetracycline, chlortetracycline, doxycycline, etc. chloramphenicol antibiotics, e.g., chloramphenicol, thiamphenicol Macrolide antibiotics, such as erythromycin, leucomycin, odorless erythromycin, etc. mycin, acetylspiramycin, medimycin, josamycin, azithromycin clarithromycin, dirithromycin, roxithromycin, telithromycin, etc. glycopeptide antibiotics, such as vancomycin, norvancomycin, teicopla quinolone antibiotics, such as norfloxacin, ofloxacin, ciprofloxacin, etc. Sacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalizin cis-, levofloxacin, moxifloxacin, besifloxacin; nitroimidazoline antibacterial antibiotics, such as metronidazole, tinidazole, ornidazole, etc.; cin antibiotics, such as rifampicin; echinocandin antibiotics; polyene antibiotics Pyrimidine antibiotics; Arylamine antibiotics; Azole antibiotics; Other antibiotics Substances: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin Isocin, mitomycin, actinomycin D, bleomycin, doxorubicin, isocin Niazid, pyrazinamide, cyclosporine, polymyxin B combinations e.g. polymyxin B Polymyxin B / trimethoprim, Polymyxin B / bacitracin, Polymyxin B / neomycin / gramicidin, etc.

[0168] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, sarcoid Lubarsan, azithromycin, azlocillin, aztreonam, bacitracin, capret Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Phallothin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, clopidogrel Ramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin fluticasone, clofazimine, cloxacillin, colistin, cycloserine, dalfopristine dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, Xicycline, erythromycin, ethambutol, ethionamide, flucloxacillin fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isononyl Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, metronidazole Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupirone Leucine, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin penicillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Rifabutin, rifampicin, rifamycin fampin), rifapentine, rifaximin, roxithromycin, sulfadia Silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavan Telavancin, telithromycin, temocillin, tetracycline, Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, troleandomycin, vancomycin, enoxacin, lomefloxacin cin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moxa Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicid, Falazine, cephapirin, cephalothin, cefmetazole, cefotaxime, moxara Cettam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Radezolid zolid, Torezolid, Oritavancin ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Teixobactin, Malacidins and The antibiotic may be selected from any of the following combinations: in the form of a pharmaceutically acceptable salt or a mixture of its corresponding pharmaceutically acceptable salts; The antibiotics may be prepared and administered by their known routes of administration, and in particular There are no restrictions.

[0169] Anti-VEGF drugs are generally biopharmaceuticals that target VEGF, such as ranibizumab and Afri Includes Bercept, Bevacizumab, Conbercept, etc.

[0170] Treatment method The compounds of the present disclosure can be used to treat infections caused by microorganisms such as Bacillus megaterium (e.g., eye infections). therapeutic activity to treat and / or prevent diseases or disorders associated with the intraocular space, e.g., As shown in the Examples section, representative compounds of the present disclosure are useful as in vivo In the Vitro test, it showed a strong effect of killing or inhibiting the representative microorganism Bacillus megaterium. Further, the examples demonstrate the use of batilla bacillosum in vivo, e.g., in the rhesus monkey model of the present application. Antibiotics such as vancomycin can kill or inhibit S. megaterium. We show that it can reduce the drusenoid lesions induced by C. megaterium.

[0171] Thus, in embodiments, the present disclosure provides a method for treating a disease using a compound of the present disclosure or a pharmaceutical composition of the present application. and treating infections caused by the microorganisms of the present invention, such as Bacillus megaterium, and Further provided are methods for treating or preventing infection-related diseases or disorders (e.g., AMD). .

[0172] Unless otherwise specified, in any of the foregoing embodiments of the present application, the infection may include an ocular infection, for example, in the intraocular space. Unless otherwise specified, in any of the foregoing embodiments of the present application, the microorganism may include Bacillus megaterium. In some embodiments, the microorganism is selected from the group consisting of Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythroides, and the like. Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae.

[0173] In some embodiments, the compounds of the present disclosure inhibit the growth of the microorganisms of the present application, such as Bacillus megaterium. In some embodiments, the present invention can be used to kill or inhibit the growth of bacteria. The compounds shown are useful in treating AMD, including drusen manifestations (hard drusen, soft drusen, mixed Dry or wet age-related macular degeneration with drusen and / or degenerative drusen, e.g. For example, to treat or prevent dry or wet age-related macular degeneration with soft drusen symptoms. The compounds of the present disclosure may be used alone, for example, as described herein. They may also be used in combination with each other and with other antibiotics and / or anti-VEGF agents. It may also be used in combination.

[0174] In some embodiments, the present disclosure provides a method for killing the microorganisms of the present disclosure, such as Bacillus megaterium. In some embodiments, the method comprises: The method includes contacting the microorganism with an effective amount of a compound of the present disclosure or the pharmaceutical composition of the present application. In some embodiments, the contacting may be in vitro, ex vivo, or in vivo.

[0175] In some embodiments, the present disclosure provides a method for administering to a subject in need thereof a microorganism, such as a microbial Further provided are methods for killing or inhibiting the growth of Bacillus megaterium. In some embodiments, the method includes administering to a subject a compound of the present disclosure (e.g., Formula I, II, III, I V-1, IV-2, V, a compound of any of these subformulas, or any of compounds 1 to 8 or a pharmaceutically acceptable salt or ester thereof) to the subject. Unless otherwise indicated, in any of the above embodiments of the present application, the method comprises administering to a subject a compound selected from Compounds 1-8. administering to a subject a compound or a pharmaceutically acceptable salt or ester thereof Unless otherwise indicated, in any of the foregoing embodiments of the present application, the method may further comprise administering to a subject a pharmaceutical composition. The pharmaceutical composition may further comprise a step of administering to a subject a compound selected from Compounds 1 to 8. or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the compound or pharmaceutical composition is administered to a subject, e.g., to the eye ( Effectively kills microorganisms in the blood and / or gastrointestinal tract, e.g., the intestine, In some embodiments, the subject is treated with AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk for developing AMD. The examiner's eye is infected with the microorganism in question, e.g., Bacillus megaterium. In one embodiment, the method includes administering to a subject an infection of the intraocular space, e.g., a microorganism, e.g., Bacillus megaterium. In some embodiments, the method further comprises identifying or having identified the ammonium salt. The subject may further be administered an antibiotic and / or an anti-VEGF drug, as described herein. In such embodiments, the antibiotic and / or anti-VEGF agent is a compound of the present disclosure or The pharmaceutical compositions may be administered to a subject simultaneously or sequentially in any order.

[0176] In some embodiments, the present disclosure provides a method for treating or preventing AMD in a subject in need thereof. In some embodiments, the method comprises administering a compound of the present disclosure (e.g., Compounds of formula I, II, III, IV-1, IV-2, V), compounds of any of these subformulas or any of Compounds 1 to 8, or a pharmaceutically acceptable salt or ester thereof, Unless indicated to the contrary, any of the foregoing embodiments of the present application may include administering to a subject a therapeutically effective amount of In an embodiment, the method comprises administering to a subject a compound selected from Compounds 1-8 or a pharmaceutically acceptable salt thereof, or Unless otherwise indicated, the present application In any of the above embodiments, the method further comprises administering the pharmaceutical composition to a subject. The pharmaceutical composition may comprise a compound selected from Compounds 1 to 8 or a pharmaceutically acceptable salt thereof. In some embodiments, the method is free of or substantially free of salts or esters. For example, administering antibiotics and / or anti-VEGF drugs to a subject as described herein. In some embodiments, AMD is characterized by drusen syndrome (hard drusen). dry drusen with drusen, soft drusen, mixed drusen and / or degraded drusen or wet age-related macular degeneration, such as dry or wet age-related macular degeneration with soft drusen symptoms In some embodiments, the method comprises administering to the subject, for example, a drug to the intraocular space, Identifying or identifying a microorganism, such as Bacillus megaterium, as infecting the In some embodiments, the subject further comprises, for example, a microorganism, such as a microorganism of the present application, in the intraocular space. In some embodiments, the method further comprises: For example, the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, e.g., intestine An amount that effectively kills or inhibits the growth of microorganisms such as Bacillus megaterium and administering the compound or pharmaceutical composition to the subject.

[0177] The administration of the present application is not limited to any particular route of administration. For example, in some embodiments, The administration may be oral, nasal, topical, intraocular, intravitreal, transdermal, pulmonary, inhalation, buccal, sublingual, or intraperitoneal. The administration may be intravenous, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In embodiments, administration may be oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, administration is intravitreal. It is inside.

[0178] Dosage protocols, such as dosage and frequency, depend on multiple factors, e.g., what is being treated, the disease being treated, and the disease or disorder and its severity, the composition of the compound contained therein, the administration time, the administration route, and the duration of treatment may vary depending on the compound's potency, its clearance, and whether other medications are administered concomitantly. do.

[0179] extract In one aspect, the present disclosure further provides extracts of several traditional Chinese medicines (TCM) with antibacterial activity. The term traditional Chinese medicine is, for example, in the corresponding chapter of the Pharmacopoeia of the People's Republic of China (current edition). As stated, it should be interpreted broadly to include herbal and non-herbal medicines. As described in detail in , multiple species of TCM are used as the representative microorganism of the present invention, Bacillus megaterium. Some of the isolated components from these TCMs were found to be active against Bacillus subtilis. The extract itself is further identified as having activity against S. megaterium. They are useful for treating organism infections and related diseases or disorders such as AMD.

[0180] Thus, in some embodiments, the present disclosure provides a method for treating AM in a subject in need thereof. The present invention provides a method for treating or preventing D, the method comprising using licorice (e.g., Glycyrrhiza glabra) za uralensis), Chinese peony (e.g., Cynanchum otoph yllum), forsythia (e.g., Forsythia suspense), (e.g., Citrus aurantium L.), Rehman nia glutinosa Libosch), Chimpi (e.g., Citrus re ticulata Blanco), and Sanshichi (e.g., Panax notogi administering to the subject an extract from one or more TCMs selected from In some embodiments, AMD is characterized by drusen symptoms (hard drusen, soft drusen, etc.). Dry or wet aging with drusen, mixed drusen, and / or degenerated drusen Macular degeneration, including dry or wet age-related macular degeneration with soft drusen symptoms In some embodiments, the method may involve administering to a subject, for example, a microorganism, such as a microorganism of the present application, to the intraocular space. For example, the method further includes identifying Bacillus megaterium as an infecting strain or identifying the strain. In some embodiments, the subject may administer, for example, a microorganism of the present application, e.g., Bacillus subtilis, to the intraocular space. Infected with Megatherium.

[0181] In some embodiments, the present disclosure provides a method for killing the microorganisms of the present application in a subject in need thereof. and methods for killing or inhibiting the growth of the microorganisms of the present application, such as Bacillus megaterium. The present invention provides a method for treating a licorice (e.g., Glycyrrhiza glabra) infection, the method comprising: uralensis), Chinese peony (e.g., Cynanchum otophyllum lum), forsythia (e.g., Forsythia suspense), and Japanese koko (e.g., Citrus aurantium L.), Rehmannia glutinosa (e.g., Rehmannia glutinosa), a glutinosa Libosch), Citrus reti culata Blanco), and Sanshichi (e.g., Panax notogins eng) to the subject. In some embodiments, the subject has AMD. The subject does not have AMD. In some embodiments, the subject develops AMD. In some embodiments, the subject's eye is infected with a microorganism of the present application, such as Bacillus meliloti. In some embodiments, the method comprises administering to a subject, e.g., an intraocular cavity, an infection of the subject with gallbladder disease. Identifying the microorganism, e.g., Bacillus megaterium, as infecting the In some embodiments, the subject is further administered an antibody, e.g., as described herein. A biological substance and / or an anti-VEGF drug is further administered.

[0182] In some embodiments, the extract may be an extract of a single TCM. In some embodiments, the method includes administering to a subject licorice (e.g., Glycyrrhiza glabra) In some embodiments, the method comprises administering an extract of A. ralensis. The method involves giving subjects white peony (e.g., Cynanchum otophyllum) In some embodiments, the method comprises administering to the subject a lentil extract. administering an extract of Forsythia suspense In some embodiments, the method comprises administering to the subject a citrus fruit (e.g., Citrus a In some embodiments, the method comprises administering an extract of (A. urantium L.). The method includes administering to a subject Rehmannia glutinosa (e.g., Rehmannia glutinosa L. bosch), Chimpi (e.g., Citrus reticulata Blanco) In some embodiments, the method comprises administering to the subject an extract of The method includes administering an extract of Panax notoginseng (e.g., Panax notoginseng). nothing.

[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 cultivating licorice (e.g., Glycyrrhiza iza uralensis), Chinese peony (e.g., Cynanchum otop hyllum), forsythia (e.g., Forsythia suspense), kiko Citrus aurantium L.), Rehmannia glutinosa (e.g., Rehma nnia glutinosa Libosch), Chimpi (e.g., Citrus r eticulata Blanco), and Sanshichi (e.g., Panax notog Injecting two or more TCM extracts selected from In some embodiments, the method includes (a) cultivating licorice (e.g., Glycyrrhiza glabra) rhiza uralensis), Chinese peony (e.g., Cynanchum ot ophiollum), forsythia (e.g., Forsythia suspense), Citrus aurantium L., Rehmannia glutinosa (e.g., Rehmannia glutinosa), mannia glutinosa Libosch), Chimpi (e.g., Citrus reticulata Blanco), and Sanshichi (e.g., Panax not and (b) one or more TCMs derived from other TCMs. In some embodiments, the method comprises administering the extract to a subject. Each independently, Glycyrrhiza, White Peony, Forsythia, Anthurium, Rehmannia, Citrus Pepper, and and Sanshichi, any combination of 1-7 types (not all TCM), and optionally (b) administering to the subject an extract from one or more other TCMs. Includes flops.

[0184] The extracts of this application are generally prepared according to the general practice of TCM. See, for example, the Examples section. When two or more TCMs are used, each TCM (or any of the TCMs) Subgroups are extracted separately and then these extracts are combined, or two The extract may be prepared in a manner that extracts the above TCMs simultaneously. In some embodiments, non-aqueous extracts are also useful. In CM, parts of several types of plants, such as leaves, stems, roots, fruits, seeds, etc., are useful. In embodiments, when applied, the extract is not limited to any particular part of the TCM plant. .

[0185] The extracts of the present application may be present or 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. The extract may be made into capsules, tablets, powders, etc. and administered accordingly, usually via oral administration. The administration of the extract may follow typical practices for TCM and may be administered orally. The administration route is not limited to the dosage protocol, e.g., amount and frequency, depending on multiple predisposing factors, e.g., treatment. the person receiving treatment, the disease or disorder to be treated and its severity, the composition of the extract containing it, and the administration time, route of administration, duration of treatment, potency of the extract, its clearance and simultaneous administration of other drugs In some embodiments, the extract may be administered to a subject. For example, the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, e.g., intestine An amount that effectively kills or inhibits the growth of microorganisms such as Bacillus megaterium It is administered at .

[0186] antibiotics As discussed herein, the present invention is based in part on the understanding that the intraocular environment is not sterile, and This is based on the unexpected discovery that the intraocular microbiota may be a causative factor in AMD. Therefore, any antibiotic, such as those known in the art, may be used to treat infection with the microorganisms of the present application. and may be used to treat or prevent AMD. The present disclosure provides a method for administering a microorganism of the present application, such as Bacillus megaterium, to a subject in need thereof. and methods for killing or inhibiting the growth of bacteria, and methods for preventing infection (e.g., visual acuity) of the microorganisms of the present invention. Methods for treating infections, e.g., in the intraocular space, and / or diseases or conditions associated with microorganisms or infections Further provided is a method of treating or preventing a disorder, such as AMD, comprising administering an antibiotic to a subject. In some embodiments, the method comprises administering an effective amount of a commercially available Any antibiotic, including those approved by the US FDA, can be used. In some embodiments, the antibiotic is characterized as a broad-spectrum antibiotic. In some embodiments, the antibiotic is an antibiotic against gram-positive bacteria. In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk for an eye infection, e.g., a microbial infection of the present application. For example, one infected with Bacillus megaterium. AMD is characterized by drusen symptoms (hard drusen, soft drusen, mixed drusen and / or Dry or wet age-related macular degeneration (including degenerative drusen), such as soft drusen In some embodiments, the method may be for dry or wet age-related macular degeneration. The method involves infecting a subject, for example, in the intraocular space, with a microorganism of the present application, for example, Bacillus megaterium. In some embodiments, the method further comprises identifying or having identified the subject as having For example, the intraocular space is infected with the microorganism of the present application, e.g., Bacillus megaterium. In some embodiments, the subject may have been administered an anti-VEGF drug, for example, as described herein. do.

[0187] The compounds of the present disclosure (see, for example, the Compounds section) generally have antibacterial activity and, therefore, are useful in the treatment of antibiotics. However, the antibiotics described in this chapter may be used in combination with compounds of the present disclosure (e.g., In some embodiments, the compound may be independent of an antibiotic (e.g., as defined herein). In some embodiments, the antibiotic is not a compound of the present disclosure. In some embodiments, the antibiotic and the compound of the present disclosure are used together in a combination therapy, These may be administered simultaneously (e.g., as a single dosage form) or in any order to subjects who require them. may be administered sequentially.

[0188] In some embodiments, the antibiotic is a β-lactam antibiotic, an aminoglycoside antibiotic, or Substances, tetracycline antibiotics, chloramphenicol antibiotics, macrolides Antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics substances, rifamycin antibiotics, echinocandin antibiotics, polyene antibiotics, Imidine antibiotics, allylamine antibiotics, azole antibiotics, or combinations thereof It may also be a combination.

[0189] In some embodiments, the antibiotic is a β-lactam antibiotic, such as a penicillin ( For example, penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafsili penicillin, oxacillin, penicillin G, piperacillin, pivampicillin, pivmecillinam, Carcillin, cephalosporins such as cefastril, cefadroxil, cephalexin Cephaloglycin, Cephalonium, Cephaloridine, Cephalothin, Cefapyridine Cefatrizine, cefazaflur, cefazedone, cefazolin, cephradizine, Floxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cef Onicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, Cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime , cefteram, ceftibuten, ceftiofur, ceftaroline, ceftizoxime, ceftri Axon, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam , cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, cefta Lorin, cefacromedine, cephaloram, cefparole, cefcanel, cefedrol , cefenpidon, cefetrizole, cefibitril, cefmatilen (cefmati len), cefmepidium, cefovecin, cefoxazo Cefurotil, cefsumid, cefratime, ceftioxide, thienamycins, mono Bactams, β-lactamase inhibitors, methoxypenicillins; aminoglycosides Substances such as streptomycin, gentamicin, kanamycin (e.g. A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin Isomycin C, Neomycin E), Ribomycin, Micronomycin, Azithromycin, Dimethicone Bekacin, sisomicin, netilmicin, paromomycin, bramycin, etc.; Tetrasamine Icrine antibiotics, such as tetracycline, oxytetracycline, chlortetracycline cycline, doxycycline, and the like; chloramphenicol antibiotics, such as chloramphenicol thiamphenicol, thiamphenicol, etc.; macrolide antibiotics, such as erythromycin Syn, leucomycin, odorless erythromycin, acetylspiramycin, medimicin thromycin, josamycin, azithromycin, clarithromycin, dirithromycin, loxacin cysthromycin, telithromycin, etc.; glycopeptide antibiotics, such as vancomycin quinolone antibiotics, such as norfloxacin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, such as norfloxacin ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, eno fluoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, such as metronidazole and tinidazoline rifamycin antibiotics, such as rifampicin; echinococcus Polyene antibiotics; Pyrimidine antibiotics; Arylamine antibiotics azole antibiotics; other antibiotics: fosfomycin, capreomycin, cyclomycin Serine, lincomycin, clindamycin, mitomycin, actinomycin D, leomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymyxin Polymyxin B combinations, such as polymyxin B / trimethoprim, polymyxin B / bacitra may contain one or more of the following: polymyxin B / neomycin / gramicidin, etc. .

[0190] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, sarcoid Lubarsan, azithromycin, azlocillin, aztreonam, bacitracin, capret Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Phallothin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, clopidogrel Ramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin fluticasone, clofazimine, cloxacillin, colistin, cycloserine, dalfopristine dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, Xicycline, erythromycin, ethambutol, ethionamide, flucloxacillin fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isononyl Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, metronidazole Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupirone Leucine, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin penicillin, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Rifabutin, rifampicin, rifamycin fampin), rifapentine, rifaximin, roxithromycin, sulfadia Silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telavan Telavancin, telithromycin, temocillin, tetracycline, Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, troleandomycin, vancomycin, enoxacin, lomefloxacin cin, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moxa Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicid, Falazine, cephapirin, cephalothin, cefmetazole, cefotaxime, moxara Cettam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Radezolid zolid, Torezolid, Oritavancin ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Teixobactin, Malacidins and A combination of these may be selected.

[0191] In some embodiments, the antibiotic is administered to a subject, e.g., to the eye (e.g., the intraocular space) of the subject, The present invention relates to a method for effectively inhibiting the microorganisms of the present invention, such as Bacillus megaterium, in the blood and / or digestive tract, such as the intestine. The agent is administered in an amount that effectively kills or inhibits the growth of the organism.

[0192] The antibiotic may be in any form, such as in the form of a pharmaceutically acceptable salt thereof or It may also be in the form of a mixture of the corresponding pharmaceutically acceptable salts. The formulation can be prepared and administered by any route, and there are no particular limitations. Administration may be oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous. In embodiments, administration is oral, hi some embodiments, administration is intravitreal.

[0193] Dosing protocols, e.g., amount and frequency, depend on several factors, e.g., the type of person being treated, the type of person being treated, and the type of person being treated. Disease or disorder and its severity, antibiotic composition contained, administration time, administration route, duration of treatment Depending on time, antibiotic efficacy, its clearance, and whether other medications are administered concomitantly, Change.

[0194] Alternative Exemplary Embodiments In some aspects, the present disclosure provides a method for generating a model and a model generated by the method. In another aspect, the present application relates to a method for screening pharmaceuticals and the identification thereof. In some embodiments, the present disclosure provides a method for modeling and pharmaceutical preparations. Concerning the use of microorganisms in screening.

[0195] In one aspect, the present application discloses a method for producing a model, the method comprising infecting a model carrier with a microorganism. The microorganism may be a bacterium, an archaea, a protist, a fungus, a virus, or any of these. Preferably, the microorganism comprises a bacterium, and the cell The bacteria are Clostridium, Acinetobacter, etobacter, Streptococcus, Manhe Mannheimia, Fibrobacter, Prevotella, Campylobacter r), Actinomyces, Hymenobacter obacter, Escherichia, Tischerella ssierella, Klebsiella, Porphyromonas (Porphyromonas), Azospira, Achimarina quimarina), Achromobacter, Acidi Acidithiobacillus, Burkholderia holderia, Marinobacter, Treponema (Treponema), Actinosporangium ), Vibrio, Ruminococcus, Methionina Methanobrevibacter, Shigella gella), Frankia, Anaeroplasma asma), and one or more species selected from the genus Coprococcus It's okay to have one.

[0196] In some preferred embodiments, the bacteria is selected from the group consisting of Clostridium tetanus, Clostridium perfringens, Clostridium botulinum, Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacarolitica, asacharolytica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabirds, Campylobacter Uppsala, Campylobacter concisely, Campylobacter fetus, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontolyticus odontolyticus, Escherichia coli, Escherichia blattae, Escherichia fergusonii, Escherichia hermanniihermannii, Escherichia vulneris, Tissierella apical, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilence, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikovi, Ruminococcus albus, Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella bogdii, Shigella sonnei, Frankiaceae, Streptomyces albusalbus), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebreuths, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas malariae tofilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, and Finegoldia magna.

[0197] In some preferred embodiments, the bacteria is selected from the group consisting of Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebreuths, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus aureus, and the like. Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, and Finegoldia magna.

[0198] In some preferred embodiments, the bacterium is Pseudomonas putida, Bacillus megaterium, The bacteria are one or more selected from the group consisting of Propionibacterium and Propionibacterium acnes. In morphology, the bacterium is Bacillus megaterium.

[0199] In some preferred embodiments, the present disclosure provides a method for creating a model for cataract (Cat). Regarding the method, the method is for the production of Pseudomonas mendocina, Chitococcus sedentarius, A. Lycycliphilus denitrificans, Achromobacter xyloxidans, Sphi Mycobacterium chaponicum, Mycobacterium abscessus, Arthrobacter aureus rescens, Prevotella dentalis, Sinorhizobium meliloti or Acidovorac infecting the model carrier with one or more microorganisms selected from S. eubreus. include.

[0200] In some preferred embodiments, the present disclosure relates to methods for generating models for age-related macular degeneration (AMD), the methods comprising: generating a model for Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus aureus, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus aureus, Bacillus cereus, Bacillus megaterium, Bacillus cereus ... Faecium The method includes the step of infecting a model carrier with one or more microorganisms selected from the group consisting of Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

[0201] In some preferred embodiments, the present disclosure provides a method for generating a model for glaucoma (GLA). Regarding the method, the method is for the treatment of Acinetobacter baumannii, Acinetobacter calcoaceticus Bacillus thurii, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thurii ingensis, Citrobacter koseri, Diadobacter fermentans or Serratii A step of infecting a model carrier with one or more microorganisms selected from A. marcescens Includes flops.

[0202] In some preferred embodiments, the present disclosure provides a model for Behçet's disease (BD). Regarding the method for producing the same, the method includes the steps of: , Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus Rispertus, Burkholderia multivorans, Lactobacillus delbrueckii or Met Infect the model carrier with one or more microorganisms selected from Iothermus sylvanus (D). The method includes the step of:

[0203] In some preferred embodiments, the present disclosure provides a method for treating Vogt-Koyanagi-Harada syndrome (VKH). The present invention relates to a method for producing a model for Escherichia coli, Micrococcus luteus, Bacillus subtilis, bacterium, Corynebacterium auricum or Finegoldia magna The method includes the step of infecting a model carrier with one or more species of microorganism.

[0204] Model carriers include human and non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, It may comprise one or more of the following: body fluid culture, cells, viruses, enzymes, and media. Animals may include any mammal used for laboratory, pet, or economic purposes. Mammals include mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, and the like. Tissues, tissue sections and tissue extracts may be derived from any part of the subject or test animal, including the nose and tongue. In some embodiments, the tissue comprises a tissue, tissue section, or tissue extract of a subject. Includes the zona, ciliary body, ciliary body and ciliary muscle, vitreous body, retina, choroid, optic nerve, lens, or iris. In some embodiments, the tissue extract comprises DNA, RNA, or protein. In embodiments, the body fluid is lymphatic fluid, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood In some embodiments, the body fluid culture comprises an AH and a VH culture. .

[0205] In another aspect, the present application discloses the use of microorganisms in the generation of models, and in particular, The model is generated by infecting a model carrier with the microorganism. The defined range of carriers is as described herein.

[0206] In a further aspect, the present application provides a method for producing a model carrier by infecting the carrier with a microorganism. The defined range of microorganisms and model carriers is as described herein. is.

[0207] In a further aspect, the present application discloses a method for screening a pharmaceutical agent, the method comprising: The method includes the steps of (1) applying the model and (2) analysing the results. The method involves creating a model by infecting a model carrier with a microorganism. Step (1) of applying drugs to the model (2) of analyzing the results ( 3) Pharmaceuticals that kill or inhibit microorganisms in the model have therapeutic or preventive effects. Then it can be identified.

[0208] The microorganisms include bacteria, archaea, protists, fungi, viruses, or combinations thereof; Preferably, the microorganism comprises a bacterium, the bacterium being a member of the genus Clostridium. , Acinetobacter spp., Streptococcus spp., Mannheimia spp., Fibrobacter spp., Levotella spp., Campylobacter spp., Actinomyces spp., Hymenobacter spp., Escherichia coli Genus A, Genus Tissierella, Genus Klebsiella, Genus Porphyromonas, Genus Azopyra, Genus Achimarina genera, Achromobacter, Acidothiobacillus, Burkholderia, Marinobacter genus, Treponema genus, Actisporangium genus, Vibrio genus, Ruminococcus genus, Methanosarcina Brewer's genus, Shigella genus, Frankia genus, Anaeroplasma genus, and Coprococcus It may be one or more species selected from the genus.

[0209] In some preferred embodiments, the bacteria is selected from the group consisting of Clostridium tetanus, Clostridium perfringens, Clostridium botulinum, Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacarolitica, asacharolytica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabirds, Campylobacter Uppsala, Campylobacter concisely, Campylobacter fetus, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontolyticus odontolyticus, Escherichia coli, Escherichia blattae, Escherichia fergusonii, Escherichia hermanniihermannii, Escherichia vulneris, Tissierella apical, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brasilence, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikovi, Ruminococcus albus, Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella bogdii, Shigella sonnei, Frankiaceae, Streptomyces albusalbus), Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebuleus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus aureus Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, and Finegoldia magna.

[0210] In some preferred embodiments, the bacteria is selected from the group consisting of Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebreuths, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus aureus, and the like. Faecium , Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, and Finegoldia magna.

[0211] In some preferred embodiments, the bacterium is Pseudomonas putida, Bacillus megaterium, The bacterium may be one or more selected from the group consisting of Propionibacterium acnes and Propionibacterium acnes.

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

[0213] Model carriers include human and non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, The cells may be one or more of a body fluid culture, a cell, a virus, an enzyme, and a medium. Animals include any mammal used for laboratory, pet, or economic purposes. Exemplary Non-Human Mammals are mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, monkeys or Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, nose, and tongue. Tissues, tissue sections and tissue extracts include tissues, tissues derived from any part of a subject or test animal. In some embodiments, the tissue comprises a tissue section or tissue extract of the subject. The retina, choroid, optic nerve, lens, and iris are all parts of the eye. In embodiments, the tissue extract comprises DNA, RNA, or protein. So, body fluids are lymphatic fluid, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or In some embodiments, the body fluid cultures include AH and VH cultures.

[0214] Medicines include small molecule medicines, chemical medicines, large molecule medicines, biological medicines or natural medicines (traditional Chinese medicines). The composition may contain one or more of the following:

[0215] Preferably, the pharmaceutical agent is a drug for treating age-related macular degeneration (AMD), Behcet's disease (BD), Vogt's disease (VD), or ·Koyanagi-Harada syndrome (VKH), uveitis, retinal disease, keratoconjunctivitis sicca, sympathetic ophthalmitis, Includes cataracts, conjunctivitis, meibomian gland cysts, glaucoma, and floaters It has a therapeutic effect on intraocular diseases or disorders.

[0216] Chemical drugs include β-lactam antibiotics: penicillins, cephalosporins, β-lactams, Tamase inhibitors and methoxypenicillins; aminoglycoside antibiotics: streptomycin cin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, tetracycline antibiotics: tetracycline, oxytocin Tetracycline and chlortetracycline; chloramphenicol antibiotics: Loramphenicol and thiamphenicol; Macrolide antibiotics: Erythromycin Leucomycin, odorless erythromycin, acetylspiramycin, medimycin , josamycin and azithromycin; glycopeptide antibiotics: vancomycin, Norvancomycin and teicoplanin; quinolone antibiotics: norfloxacin, off loxacin, ciprofloxacin, pefloxacin and gatifloxacin; nitroimidazolinone Antibiotics: metronidazole, tinidazole and ornidazole; rifamycin Antibiotics: rifampicin; echinocandin antibiotics, polyene antibiotics, pyrimidin Antibiotics: benzodiazepines, ... Sufomycin, cycloserine, lincomycin, clindamycin, mitomycin, Actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine or a combination thereof.

[0217] The biological pharmaceutical may be an antimicrobial peptide, which has an antimicrobial activity against insects. Microbial peptides: Lepidopteran antimicrobial peptides, Dipteran antimicrobial peptides, Coleopteran antimicrobial peptides , Hymenoptera antimicrobial peptides and silkworm antimicrobial peptides; mammalian antimicrobial peptides: porcine antimicrobial Peptides, ovine antimicrobial peptides, bovine antimicrobial peptides and human antimicrobial peptides; amphibian antimicrobial Peptides: Xenopus; Antibacterial peptides derived from fish, mollusks or crustaceans: Hypocrea Antibacterial peptides, mussel antibacterial peptides, and shrimp antibacterial peptides; bacterial antibacterial peptides bacitracin, gramicidin, polymyxin and nisin; plant antimicrobial peptides, or It may also include combinations of these.

[0218] Natural medicines include Astragalus and Polygonatum , Angelica, Sanqi, Rhizome a Imperatae), Rhubarb Charcoal, Silk Curcuma aromatica, Fritillary, Yokui Coix Seed, Pinellia, Calci ned ancient ink), Danshen (Salvia Miltiorrhiz a), Arnebia euchroma, Radix Isatidis), Houttuynia, Honeysuckle Scutellaria (Scutellaria chinensis), Coptis (Rhizoma Coptis), Scutellaria chinensis (Scutellaria chinensis) laria), Dandelion, Purslane, Hawthorn, Isatidis Folium, Forsythia Fructus Forsythiae, Herba Artemis siae Capillaris), Andrographis Pan iculata Nees), Radix Bupleuri, Rhubarb (R hubarb), Shikisou (Euphorbia Humifusa), Byakubu (St emonae), Taisan (Garlic), Phellodendron bark (Cortex Phellodendron endri), Eucommia ulmoides, Cortex fraxini ), Fructus Cnidii, Galla Chin ensis), Viola yedoensis makino, Uba Fructus Mume, Licorice (Radix Glycyrrhizae) , Pericarpium Granati, Schisandra dra chinensis), Spina gleditsiae, Terminalia chebula, Sophora flavescens cens), Cortex pseudolaricis, Inyokaku ( Epimedium), Seiko (Artemisia apiacea Hance) , extracts thereof or combinations thereof.

[0219] The pharmaceutical agent of the present disclosure may be an oral pharmaceutical agent, an injectable pharmaceutical agent, or a topical pharmaceutical agent. includes mucosal medications, preferably eye drops.

[0220] The pharmaceutical preparations of the present disclosure may be in the form of solutions, tablets, pills, capsules, injections, powders, injectable powders, patches, It may be in the form of a coating agent or a preparation for mucosal administration, preferably eye drops, eye ointment or eye spray. Formulations, etc.

[0221] In some preferred embodiments, the present disclosure provides a method for treating or preventing cataracts (Cat). Regarding the pharmaceutical screening method of the above, the steps of the method are as follows: (1) Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus Sphingobium denitrificans, Achromobacter xyloxidans, Sphingobium sphingobium japonicum, Mycobacterium abscessus, Arthrobacter aurescens, Pre Botela dentalis, Sinorhizobium meliloti or Acidovorax ebreuthus Creating a model by infecting a model carrier with one or more of the following microorganisms: . (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model are used in cat patients. The compound may be identified as having a therapeutic or prophylactic effect against

[0222] In some preferred embodiments, the present disclosure relates to a method for screening a pharmaceutical agent for treating or preventing age-related macular degeneration (AMD), the steps of the method being as follows: (1) Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus Faecium The model is created by infecting a model carrier with one or more of the following microorganisms: Cytophaga hutchinsonii, Bacillus licheniformis, or Xanthomonas oryzae. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be useful for AMD patients. The compound may be identified as having a therapeutic or prophylactic effect against

[0223] In some preferred embodiments, the present disclosure provides a method for treating or preventing glaucoma (GLAUCOMA). Regarding the pharmaceutical screening method of the above, the steps of the method are as follows: (1) Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Trobacter koseri, Diadobacter fermentans or Serratia marcescens Models are created by infecting model carriers with one or more of the following microorganisms: do. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model are effective against GLA patients. The compound may be identified as having a therapeutic or prophylactic effect against

[0224] In some preferred embodiments, the present disclosure provides a method for treating or preventing Behcet's disease (BD). Regarding the method for screening pharmaceuticals for the treatment of cancer, the steps of the method are as follows: (1) Sphingomonas wichii, Klebsiella pneumoniae, Pseudomonas fuscata Luorescens, Ralstonia picketii, Lactobacillus crispatus, Burkho Ruderia multivorans, Lactobacillus delbrueckii or Meiothermus sylva The model was prepared by infecting a model carrier with one or more of the following microorganisms: Create a. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit the microorganisms in the model are useful for BD patients. The compound may be identified as having a therapeutic or prophylactic effect against the compound.

[0225] In some preferred embodiments, the present disclosure provides a method for treating Vogt-Koyanagi-Harada syndrome (VKH). A method for screening a pharmaceutical agent for treating or preventing a disease, the method comprising the steps of: That's right. (1) Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurumcoccus Infect model carriers with one or more of the microorganisms P. samoidis or P. magna. A model is created by (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit the microorganisms in the model are useful for VKH patients. The compound may be identified as having a therapeutic or prophylactic effect against

[0226] In a further aspect, the present application discloses the use of microorganisms for screening in pharmaceuticals, including Specifically, the drug screening steps are as follows: A model is created by infecting a carrier, and then a drug is applied to the model. Screening for therapeutic or preventive effects. Defined microorganisms, model carriers, and pharmaceuticals. The ranges are as described above.

[0227] In a further aspect, the present application provides a method for producing a model by infecting a model carrier with a microorganism. The steps are to create a model, apply drugs to the model, and screen for positive drug results. and a step of screening the microorganisms. The defined ranges are as above.

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

[0229] Embodiment 1. An intraocular disease or disorder model comprising a step of infecting a model carrier with a microorganism. How to create a rule.

[0230] Embodiment 2. The method of embodiment 1, wherein the microorganism is a bacterium, an archaea, a protist, The pathogen may be a fungus, a virus, or a combination thereof.

[0231] Embodiment 3. The method of embodiment 1, wherein the model carrier is a human, non-human mammal. Mammalian animals, organs, tissues, tissue sections, tissue extracts, body fluids, body fluid cultures, cells, viruses, enzymes , and culture medium.

[0232] Embodiment 4. The method of embodiment 2, wherein the microorganism is a member of the genus Clostridium, Azotobacter, or the like. Sinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevo Terra, Campylobacter, Actinomyces, Hymenobacter, Escherichia , Tissierella spp., Klebsiella spp., Porphyromonas spp., Azopyra spp., Achimarina spp., Achromobacter spp., Acidothiobacillus spp., Burkholderia spp., Marinobacter spp., Treponema, Actisporangium, Vibrio, Ruminococcus, Methanobacter From the genera Uybaster, Shigella, Frankia, Anelloplasma, and Coprococcus The present invention includes one or more bacteria selected from the group consisting of:

[0233] Embodiment 5. The method of embodiment 4, wherein the bacterium is selected from the group consisting of Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacarolitica, Porphyromonas gingivalis, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seebard, and Campylobacter Uppsala, Campylobacter conciseri, Campylobacter fetus, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontolyticus, Escherichia coli, Escherichia blattae, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris, Tissierella apiale, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brazilense, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiorrhizobium oxydans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio meshnikovii, Ruminococcus albus, Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Frankia, Streptomyces albus, Pseudomonas mendocina, Chitococcus sedentarius, Alicycliphilus denitrificans, Achromobacter - xyloxidans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebreus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus Faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia picketii, Lactobacillus crispatus, Burkholderia multivorans, Lactobacillus delbrueckii, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimcosum, and Finegoldia magna.

[0234] Embodiment 6. The method of embodiment 1, wherein the intraocular disease or disorder is cataract, aging, or the like. From macular degeneration, glaucoma, Behçet's disease, Vogt-Koyanagi-Harada syndrome or uveitis Be chosen.

[0235] Embodiment 7. The method of embodiment 1, wherein the intraocular disease or disorder is cataract; The method includes the steps of: filus denitrificans, Achromobacter xyloxidans, Sphingobius Mycobacterium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens , Prevotella dentalis, Sinorhizobium meliloti or Acidovorax eb. The method includes the step of infecting the model carrier with one or more microorganisms selected from the group consisting of Bacillus reus.

[0236] Embodiment 8. The method of embodiment 1, wherein the intraocular disease or disorder is age-related macular degeneration, and the method further comprises treating with Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus erythroides, Faecium The method includes the step of infecting a model carrier with one or ...

Claims

1. A pharmaceutical composition for treating or preventing age-related macular degeneration (AMD) in a subject in need thereof, comprising ciprofloxacin, or a pharmaceutically acceptable salt thereof; A pharmaceutical composition further comprising a compound selected from the following compound 4 or 6, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 【Chemistry 2】

2. 10. The pharmaceutical composition of claim 1, wherein the subject has been identified as having an intraocular space infection with a microorganism selected from Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

3. 3. The pharmaceutical composition of claim 2, wherein the microorganism comprises Bacillus megaterium.

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the pharmaceutical composition is administered to the subject in an amount that effectively kills or inhibits the growth of the microorganism in the intraocular space, blood, and / or gastrointestinal tract of the subject.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered orally.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered topically, intravitreally, intramuscularly, subcutaneously or intravenously.

7. 2. The pharmaceutical composition of claim 1, wherein the compound is derived from one or more traditional Chinese medicines (TCMs) selected from Glycyrrhiza Root, Radix Paeoniae Radix, Forsythia Fruit, Radix Anthurium, Radix Rehmannia Root, Radix Qing Pi, and Radix Sanqi.

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