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

Abstract

Provided herein are screening methods and animal models relevant to ocular diseases such as age-related macular degeneration (AMD), e.g., for use in identifying candidate therapeutics for treating or preventing ocular diseases such as AMD. Also provided herein are compounds / compositions useful for killing or inhibiting the growth of microorganisms such as Bacillus megaterium. Further provided herein are methods of using the compounds / compositions to treat infections with microorganisms such as Bacillus megaterium, as well as to treat or prevent diseases or conditions associated with such infections, such as AMD.

Description

[0001] This application is a divisional application of patent application CN201980086160.3 filed on November 12, 2019, entitled "Animal Models, Screening Methods and Treatments for Intraocular Diseases or Symptoms". Technical Field

[0002] This invention generally belongs to the field of diagnostic and therapeutic techniques for eye diseases, and more specifically relates to screening methods, animal models, and methods for treating or preventing eye diseases or conditions. In various embodiments, this disclosure also relates to compounds, compositions, and methods for treating and / or preventing age-related macular degeneration (AMD) in subjects, such as human patients or vertebrates such as dogs, cats, horses, or monkeys. Background Technology

[0003] The eyes are the windows to the soul, and they are extremely important to everyone. We use our eyes every day, yet they are also very delicate. They are easily affected by various factors, leading to discomfort or disease. Common eye diseases include conjunctivitis and dry eye syndrome, while more serious intraocular diseases or conditions include cataracts (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), uveitis, and others.

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

[0005] The pathogenesis of AMD involves both genetic and environmental factors. Currently, the environmental factors that trigger local inflammation and lead to early soft drusen in AMD pathology remain unclear. Numerous studies have identified changes at loci associated with AMD susceptibility, including complement factor H (CFH), age-related macular degeneration susceptibility 2 (ARMS2), and HtrA serine peptidase 1 (HTRA1), suggesting that AMD may be an inflammatory disease.

[0006] Currently, the environmental factors that trigger local inflammation and lead to early soft drusen in AMD pathology are unclear. There is a need for improved compositions and methods for evaluating, treating, or preventing intraocular diseases or conditions in subjects such as mammals or humans. This disclosure addresses this need, as well as other related needs. Summary of the Invention

[0007] In various embodiments, the present invention relates to screening methods and animal models for a variety of eye diseases, such as human eye diseases. These screening methods and animal models are based in part on the unexpected discovery that the intraocular environment is not sterile and that certain intraocular microbiota, such as Bacillus megaterium, can be the cause of a variety of eye diseases, such as AMD.

[0008] In some embodiments, the present invention provides a screening method for identifying candidate therapeutics for the treatment or prevention of eye diseases such as AMD. This screening method may be an in vitro screening method, such as in a petri dish, or an in vivo screening method, such as using the animal models described herein.

[0009] In some embodiments, the present invention provides a screening method comprising: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; b) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally c) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the microorganisms comprise species enriched in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with an eye disease compared to a healthy subject, wherein the eye disease is selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. In some embodiments, the subject is a human subject. In some embodiments, the method is used to identify candidate therapeutics for the treatment or prevention of human eye diseases such as AMD, BD, Cat, EOS, GLA, VKH, or combinations thereof.

[0010] In some specific implementations, the screening method is used to identify candidate therapeutics for the treatment or prevention of AMD. In some implementations, the microorganisms include species that are enriched in the intraocular spaces (e.g., aqueous humor, vitreous fluid, soft drusen) of subjects with AMD compared to healthy subjects. In some embodiments, the microorganisms include one or more species selected from the following: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophagahutchinsonii, 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 comprise a mixture of microbial species substantially similar to those observed from the aqueous humor, vitreous humor, and / or soft drusen of a subject with AMD. In some embodiments, the microorganisms are derived partly or entirely from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration.

[0011] The screening methods used to identify candidate therapeutics for the treatment or prevention of other eye diseases such as BD, Cat, EOS, GLA, and VKH are similar to those described for AMD, but use different microorganisms, as detailed herein. For example, for BD, the microorganisms cultured in the presence of the test compound may typically include one or more species selected from: *Sphingomonas wittichii*, *Klebsiella pneumoniae*, *Pseudomonas fluorescens*, *Ralstonia pickettii*, *Lactobacillus crispatus*, *Burkholderia multivorans*, *Lactobacillus delbrueckii*, and *Meiothermus silvanus* (D). For Cat, the microorganisms cultured in the presence of the test compound can typically include one or more species selected from the following: Pseudomonas mendocina, Kytococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xylosoxidans, Sphingobium japonicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, and Acidovoraxebreus.For GLA, the microorganisms cultured in the presence of the test compound can typically include one or more species selected from the following: Acinetobacter baumannii, Acinetobacter calcoaceticus, Commonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Dyadobacter fermentants, and Serratia marcescens. For VKH, the microorganisms cultured in the presence of the test compound typically include one or more species selected from: *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium aureum*, and *Finegoldia magna*. In some embodiments, the microorganisms used in the screening method may also comprise a mixture of microbial species substantially similar to those observed in the aqueous humor and / or vitreous fluid of subjects with BD, Cat, EOS, GLA, or VKH, respectively. In some embodiments, the microorganisms used in the screening method may also be derived, in whole or in part, from the aqueous humor and / or vitreous fluid of subjects with BD, Cat, EOS, GLA, or VKH, respectively.

[0012] The screening methods described herein are not limited to any specific test compound or any particular type of test compound. Several exemplary test compounds are described herein. The screening methods described herein can be low-throughput, medium-throughput, or high-throughput methods, and multiple test compounds can be tested in parallel when needed. Identification in the screening methods is also not limited to any particular technique. For example, in some embodiments, identification may include identifying candidate therapeutics that prevent visible growth of microorganisms at or below the maximum test concentration. In some embodiments, identification may include identifying candidate therapeutics that prevent visible colony formation of microorganisms at or below the maximum test concentration.

[0013] The screening method described herein may further include identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with an eye disease compared to a healthy subject, wherein the eye disease is selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. For example, in some embodiments, the present invention provides a screening method comprising a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with age-related macular degeneration (AMD) compared to a healthy subject; b) culturing a microorganism comprising at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganism in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganism compared to a control.

[0014] Some embodiments of the present invention relate to methods for creating animal models of eye diseases as described herein. Animal models are typically used for human eye diseases. Animal models created by the methods described are also embodiments of the present invention.

[0015] Typically, methods for creating animal models involve introducing microorganisms and / or inactivated proteins from said microorganisms into the intraocular space of an animal's eye, wherein the microorganisms include species that are enriched in the intraocular space of a subject with an eye disease compared to a healthy subject, wherein the eye disease is selected from cataract (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), endophthalmitis (EOS), and combinations thereof, and wherein one or more symptoms causing the eye disease are introduced.

[0016] In some specific embodiments, the present invention provides a method for creating an animal model of AMD. In some embodiments, the method includes introducing microorganisms and / or inactivated proteins from said microorganisms into the intraocular space of an animal's eye, wherein the microorganisms include species enriched in the intraocular space of a subject suffering from AMD compared to a healthy subject, and wherein one or more symptoms causing AMD are introduced. The method typically introduces live microorganisms into the intraocular space of the animal. In some embodiments, the introduced microorganisms include at least live Bacillus megaterium. Preferably, the animal is a non-human primate (e.g., a monkey). In some embodiments, the animal is a rhesus macaque.

[0017] The AMD animal models described herein can also be used to identify candidate therapeutics for the treatment or prevention of AMD. For example, in some embodiments, the invention also provides a screening method comprising a) administering a test compound to an AMD animal model as described herein; b) determining the severity of one or more symptoms of the eye disease after administration; and optionally c) identifying candidate therapeutics that reduce at least one of the symptoms compared to a control.

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

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

[0020] Some embodiments involve pharmaceutical compositions comprising one or more compounds of this disclosure and optionally pharmaceutically acceptable excipients. For example, in some embodiments, the pharmaceutical composition comprises a compound of formula I, II, III, IV-1, IV-2, V, any of its subforms, or any one or more of compounds 1-8, or a pharmaceutically acceptable salt or ester thereof, for example, in an amount effective in killing, for example, the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestines, of microorganisms described herein, such as *Bacillus megaterium*, or inhibiting their growth. The pharmaceutical compositions described herein can be formulated for delivery via any known route of delivery, such as oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous administration. In some embodiments, the pharmaceutical compositions described herein may further comprise antibiotics and / or anti-VEGF drugs, for example, as described herein.

[0021] In various embodiments, this disclosure also provides methods for treating infections of microorganisms such as Bacillus megaterium (e.g., eye infections, such as those in the intraocular space) and for treating or preventing diseases or conditions associated with such infections (such as AMD) using compounds of this disclosure or pharmaceutical compositions herein.

[0022] In some embodiments, this disclosure provides methods for killing or inhibiting the growth of microorganisms such as *Bacillus megaterium* in a subject in need. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of this disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any of their derivatives, or any one or more of compounds 1-8, or their pharmaceutically acceptable salts or esters, or pharmaceutical compositions thereof). In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject has an ocular infection with microorganisms such as *Bacillus megaterium*. In some embodiments, the method further includes identifying or having identified the subject as having an infection with microorganisms such as *Bacillus megaterium*, for example, in the intraocular space. In some embodiments, the subject is further administered antibiotics and / or anti-VEGF drugs, for example, as described herein.

[0023] In some embodiments, this disclosure provides methods for treating or preventing AMD in subjects in need. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of this disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any of their subforms, or any one or more of compounds 1-8, or their pharmaceutically acceptable salts or esters). In some embodiments, the method further includes administering to the subject antibiotics and / or anti-VEGF drugs, such as those described herein. In some embodiments, AMD can be dry or wet age-related macular degeneration with drusenic symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), such as dry or wet age-related macular degeneration with soft drusenic symptoms. In some embodiments, the method further includes identifying or having identified the subject as being infected, for example, with a microorganism of this disclosure, such as Bacillus megaterium, in the intraocular space. In some embodiments, the subject is infected, for example, with a microorganism of this disclosure, such as Bacillus megaterium, in the intraocular space.

[0024] In some embodiments, this disclosure provides methods for using extracts of traditional Chinese medicines (TCMs) with antibacterial activity. In some embodiments, the method is used to kill or inhibit the growth of microorganisms described herein in a subject in need, to treat infections caused by microorganisms such as *Bacillus megaterium* (e.g., ocular infections, such as in the intraocular space), or to treat or prevent AMD. In some embodiments, the method includes administering to a subject an extract from one or more TCMs selected from: licorice (e.g., *Glycyrrhiza uralensis*), white peony root (e.g., *Cynanchum otophyllum*), forsythia (e.g., *Forsythia suspense*), immature bitter orange (e.g., *Citrus aurantium L.*), rehmannia root (e.g., *Rehmannia glutinosa* Libosch), tangerine peel (e.g., *Citrus reticulata* Blanco), and notoginseng (e.g., *Panax notoginseng*). In some embodiments, the method also includes identifying or having identified a subject infected, for example, with microorganisms such as *Bacillus megaterium* in the intraocular space. In some embodiments, the subject is infected, for example, with a microorganism described herein, such as Bacillus megaterium, within the intraocular space. The extract may be an extract of a single TCM or an extract of more than one TCM. Typically, the extract is an aqueous extract. In some embodiments, the extract may be in liquid, semi-solid, or solid form, or any other form. In some embodiments, the subject is further administered antibiotics and / or anti-VEGF drugs, for example, as described herein.

[0025] In some embodiments, this disclosure provides methods for using antibiotics to kill or inhibit the growth of microorganisms described herein, treat infections caused by microorganisms such as *Bacillus megaterium* (e.g., ocular infections, such as in the intraocular space), or treat or prevent AMD in subjects in need. In some embodiments, the method includes administering an effective amount of antibiotic to the subject, for example, as described herein. In some embodiments, any commercially available antibiotic may be used, for example, those approved by the U.S. FDA. In some embodiments, the method further includes identifying or having identified the subject as infected, for example, with microorganisms such as *Bacillus megaterium* in the intraocular space. In some embodiments, the subject is infected, for example, with microorganisms such as *Bacillus megaterium* in the intraocular space. In some embodiments, an anti-VEGF drug is further administered to the subject, for example, as described herein.

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

[0027] It should be understood that the foregoing overview and the following detailed description are merely exemplary and illustrative, and not intended to limit the invention herein. Attached Figure Description

[0028] Figure 1 This demonstrates the sensitivity of Bacillus megaterium to several antimicrobial agents.

[0029] Figure 2 This describes the culture in a liquid cooked meat medium covered with liquid paraffin.

[0030] Figure 3 This demonstrates the detection of bacteria in cultures under a standard optical microscope. Cultured *Escherichia coli* is observed under an optical microscope. The negative control consists of a sample preparation buffer without any AH or VH inoculation. Bacteria in cultured AH or VH samples (examples of cultured positive and negative samples) are observed under an optical microscope.

[0031] Figure 4 The images show ocular surface and fundus views of rhesus monkeys before and after bacterial inoculation (Propionibacterium acnes and Bacillus megaterium). The right eye (OD) and left eye (OS) of the rhesus monkeys were inoculated with Propionibacterium acnes and Bacillus megaterium, respectively. The images show ocular surface and fundus views before and 3 days after bacterial inoculation.

[0032] Figure 5 This image shows ocular surface and fundus views of rhesus monkeys before and after bacterial inoculation (Propionibacterium acnes and Pseudomonas putida). The right eye (OD) and left eye (OS) of the rhesus monkeys were inoculated with Propionibacterium acnes and Pseudomonas putida, respectively. The images show ocular surface and fundus views before and 3 days after bacterial inoculation.

[0033] Figure 6 This explains the anatomy and retinal location of subretinal injection.

[0034] Figure 7 The fundus view of a rhesus monkey on day 47 post-injection, after the monkey received subretinal inoculation with 20 CFU of AH culture, VH culture and Bacillus megaterium.

[0035] Figure 8 This demonstrates that antibiotic treatment can alter bacterial-induced drusenoid lesions in monkey retinal tissue.

[0036] Figure 9 This demonstrates the species highly enriched in the intraocular metagenomics of patients with cataracts, AMD, glaucoma, BD, and VKH, as identified using LefSe.

[0037] Figure 10 The results showed that each of compounds 1-8 effectively controlled the growth of Bacillus megaterium. Test conditions: 1 mg of compound, Bacillus megaterium, in 15 ml of culture medium at 1×10⁻⁶. 5 The concentration is 100 μl. Detailed Implementation

[0038] In various embodiments, this disclosure is based in part on the unexpected finding that the intraocular environment is not sterile and that certain intraocular microbiota can be the cause of various eye diseases such as AMD. According to this initial finding, as detailed in PCT application No. PCT / CN2018 / 112022, entitled “METHODS 1 AND COMPOSITIONS FOR ASSESSING AND TREATING INTRAOCULAR DISEASESANDDISORDERS” filed October 26, 2018 (the entire contents of which are incorporated herein by reference), such microorganisms, such as Bacillus megaterium, when administered in a live state, can activate the complement system and induce drusen-like lesions in macaques. Furthermore, killing or inhibiting the growth of such microorganisms, such as by intravitreal administration of the antibiotic vancomycin, can result in a reduction in the size of drusen-like lesions in the retinal tissue of macaques compared to controls. See also Example 9 herein. These data and results establish that agents capable of killing such microorganisms, such as Bacillus megaterium, or inhibiting their growth, can be used to treat age-related macular degeneration.

[0039] As detailed in PCT application number PCT / CN2018 / 112022, metagenomic sequencing analysis was performed on aqueous humor (AH) samples from 41 patients with cataracts (Cat), 20 with AMD, 18 with glaucoma (GLA), 9 with Behçet's disease (BD), 9 with Vogt-Koyanagi-Harada syndrome (VKH), and 8 with endophthalmitis (EOS). Interestingly, the alpha diversity and evenness of the intraocular microbiome differed significantly among these six patient types, although bacteria were the dominant component of the intraocular microbiome in all patients. Principal component analysis (PCA) of the composition of the intraocular microbiome (using all microbial species) revealed significant differences among cataract, EOS, and some glaucoma patients. However, AMD, VKH, BD, and some glaucoma patients shared indistinguishable features in their intraocular microbiome. Similarly, hierarchical cluster analysis of the abundance of functional microbial genes from all metagenomics revealed general characteristics of microbial function across ocular manifestations, with outliers within each disease group that could be classified into other disease clusters. Despite the significant individuality of the intraocular microbiome, we were able to identify characteristic bacterial species for each ocular disease group we tested. In summary, our results demonstrate that the composition and function of the intraocular microbiome can differentiate ocular diseases such as AMD, cataracts, glaucoma, BD, VKH, and EOS.

[0040] Metagenomic analysis was used to identify 14 bacterial species highly enriched in acne scars (AH) from AMD patients. While *Propionibacterium acnes* was the most abundant microorganism in AH from AMD patients, *Bacillus licheniformis* and *Bacillus megaterium* were the most enriched species among the 14 AMD-specific species in AMD AH samples. The inventors then performed PCR analysis to investigate whether the 14 AMD-specific bacteria could be detected in hard or soft drusen tissue compared to non-drusen retinal tissue from six archived ocular slides from AMD patients. The results showed that only eight bacteria could be detected, with *Propionibacterium acnes* being the most abundant species, while *Bacillus megaterium* was enriched in soft drusen. The relative abundance of *Propionibacterium acnes* in hard, soft, and dry AMD lesion tissues was comparable to that in non-drusen, non-lesion retinal tissues. The relative abundance of *Bacillus megaterium* was approximately 18-fold increased in soft drusen compared to non-drusen / non-lesion tissue, but not in AMD lesions. These data suggest a possible role for *Bacillus megaterium* in drusen formation and the pathogenesis of AMD.

[0041] Previous studies have shown that drusen contain a variety of complement components and polysaccharides, in addition to many other proteins. Furthermore, drusen components activate inflammasomes and promote the expression of IL-1β and IL-18. Therefore, the inventors first examined whether *Bacillus megaterium*, a component of drusen, could induce complement system activation in vitro and promote the secretion of IL-1β and IL-18 by acute retinal pigment epitheliitis-19 (ARPE19) cells. The inventors found that *Bacillus megaterium*, but not *Propionibacterium acnes*, significantly increased pyroptosis in RPE cells in a time-dependent manner. Activation of the complement system was confirmed by the production of the active form of C5A protein. Both bacteria induced the secretion of CFH protein by ARPE19 cells, with *Bacillus megaterium* inducing CFH more significantly than *Propionibacterium acnes*. As a result of pyroptosis, in vitro infection with *Bacillus megaterium*, but not *Propionibacterium acnes*, led to the secretion of active IL-1β and IL-18 by RPE cells. These results indicate that infection with *Bacillus megaterium* can lead to inflammation similarly observed in soft drusen.

[0042] The inventors then tested whether *Bacillus megaterium* could induce inflammation in vivo. A non-human primate, the rhesus macaque (*Macaca fascicularis*), was used as a model system taking into account the shared ocular anatomy and intraocular environment between humans and macaques. Infection of the eye with live *Propionibacterium acnes* or inoculation with its sonicated inactivated proteins did not induce significant intraocular inflammation. However, infection of the eye with live *Bacillus megaterium*, but not with its proteins, resulted in significant intraocular inflammation. Intraocular inflammation induced by live *Bacillus megaterium* was characterized by elevated expression of TNFA and IL-6, but not IFNG and IL-17A. Importantly, only live *Bacillus megaterium* was able to activate the complement system, including C5A and CFH, and induce pyroptosis of the cytokines IL-1β and IL-18 in vivo. The bacteria remained viable in the eye after the onset of inflammation, indicating that intraocular inflammation can be inherently long-lasting. In conclusion, our data demonstrate that infection with *Bacillus megaterium* can activate the complement system in vitro and in vivo and induce pyroptosis in ocular cells.

[0043] Without being bound by theory, the fact that bacteria such as *Bacillus megaterium* reside in drusen and activate local complement-mediated immune responses can explain the diverse formation of drusen between the retinas and Bruch's membrane. The major proteins found in drusen (including complement components such as C1Q and immunoglobulins) are first-line anti-infective agents. Other drusen proteins, such as fibronectin and apolipoprotein E, have recently been shown to be anti-infective agents. Therefore, drusen formation is most likely a key response of the aging retina in controlling infiltrating bacterial pathogens. Due to bacterial diversity, the shape and size of drusen can vary. In the case of hard drusen, the drusen will disappear if the infection can be cleared. However, certain pathogens, such as *Bacillus megaterium*, will induce long-term activation of the immune response in soft drusen and lead to damage to RPE cells and photoreceptors. Activation of macrophage inflammation and pyroptosis of RPE cells are protective responses against local infection, consistent with previous findings that NLRP3-mediated inflammasome activation and IL-18 production protect the retina from angiogenesis.

[0044] Not wanting to be bound by theory, the infectious etiology of AMD is also consistent with the conclusions of all genetic studies. For example, a deficiency in CFH (a negative regulator of complement activation induced by Bacillus megaterium infection) leads to uncontrolled complement activation. A deficiency in HTRA1 (a protease that produces the active form of the immunosuppressive cytokine TGF-β) leads to a reduction in local TGF-β family proteins. Both of these genetic variations can result in dysregulation of the local anti-infective response, impairing RPE cells and photoreceptors.

[0045] Furthermore, the potential differences in the pathogenic microbiota found in drusen could explain the association between different genetic risk factors and different ethnicities (e.g., Caucasians vs. Asians). Therefore, there is evidence that infectious etiologies of AMD are a mechanism that triggers early AMD pathology in older adults.

[0046] In summary, in various embodiments, the inventors have demonstrated that killing microorganisms and / or inhibiting their growth can treat and / or prevent AMD, such as dry or wet age-related macular degeneration with drusen symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), for example, dry or wet age-related macular degeneration with soft drusen symptoms.

[0047] Filtering methods

[0048] The discovery that various intraocular diseases are associated with specific microorganisms also supports screening methods for identifying candidate therapeutics for intraocular diseases such as AMD. Therefore, some embodiments of the present invention relate to a variety of screening methods. The screening methods described herein can be in vitro methods (e.g., in petri dishes) or in vivo methods (e.g., using the animal models described herein).

[0049] In some embodiments, the present invention provides a screening method comprising: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; b) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally c) identifying candidate therapeutic agents that inhibit the growth of the microorganisms compared to a control. Typically, the microorganisms include at least one species enriched in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with an eye disease compared to a healthy subject, and the eye disease is selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. In some embodiments, the method further includes d) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with an eye disease compared to a healthy subject, wherein the eye disease is selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. A healthy subject used for comparison purposes in this method refers to a subject without an eye disease. The term "control" as used in this method refers to a placebo control that does not use the test compound. Those skilled in the art will know how to conduct appropriate control experiments for comparison purposes. In any of the embodiments described herein, the subject may be a human subject to the extent that it is not directly contradictory. In any of the embodiments described herein, to the extent that it is not directly contradictory, the screening method may be used to identify candidate therapeutics for the treatment or prevention of human diseases, such as the human eye diseases described herein.

[0050] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects suffering from said eye disease, family members or close genetic relatives of subjects suffering from said eye disease, or deceased subjects known to have suffered from said eye disease; culturing one or more organisms from the sample under conditions selected from those simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; adding said compound or combination of compounds to said one or more cultures; and determining whether said compound or combination of compounds reduces the growth of said one or more cultures or reduces their population size. In some embodiments, the method may further include, based on said determination, identifying compounds or combinations of compounds that reduce the growth of said one or more cultures or reduce their population size in vitro.

[0051] In some embodiments, family members may include immediate family members of the subject, such as parents, children, or siblings. In some embodiments, family members may include individuals who have long occupied the same living space as the subject with the eye disease. In some embodiments, a close genetic relationship may include a relationship with the subject with the disease such that the relationship is within three direct generations of the subject's genetic lineage, such as the subject's great-grandparents, grandparents, parents, children, grandchildren, or great-grandchildren. In some embodiments, a close genetic relationship may include the subject's siblings. In some embodiments, a close genetic relationship may include a collateral relationship with the subject with the disease, including the subject's uncles, aunts, cousins, or nieces and nephews.

[0052] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas oryzae, Sphingosine vesiculosus, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiformis, Lactobacillus curvatureii, Burkholderia polyphaga. Lactobacillus delbrueckii, *D. sildenafil*, *Pseudomonas mendoza*, *Dermatococcus dermatophytes*, *Denitrifying lipophilic bacteria*, *Xylose-oxidizing achromobacterium*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcium acetate*, *Trichophyton mentagrophytes*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter keloidea*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; adding said compounds or combinations of said compounds to said one or more cultures; and determining whether said compounds or combinations of said compounds reduce the growth of said one or more cultures or reduce their population. In some embodiments, the method may further include, based on said determination, identifying compounds or combinations of said compounds that reduce the growth of said one or more cultures or reduce their population in vitro.

[0053] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects suffering from said eye disease, family members or close genetic relatives of subjects suffering from said eye disease, or deceased subjects known to have suffered from said eye disease; culturing one or more organisms from the sample under conditions selected from those simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; mixing said compound or combination of compounds with the solution of said one or more inactivated proteins; and determining whether said compound or combination of compounds binds to said one or more inactivated proteins.

[0054] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating ocular diseases, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects suffering from said ocular disease, family members or close genetic relatives of subjects suffering from said ocular disease, or deceased subjects known to have suffered from said ocular disease; culturing one or more organisms from the sample under conditions selected from those simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; introducing said one or more inactivated proteins into a mammalian inflammation model; introducing said compound or combination of compounds into said mammalian inflammation model; and determining whether said compound or combination of compounds reduces inflammatory activity in said model.

[0055] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas oryzae, Sphingosine vesiculosus, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiformis, Lactobacillus curvatureii, Burkholderia polyphaga, Lactobacillus delbrueckii, and Sylvatinus sylvatinus. The method comprises: *D. subtropical fever*, *Pseudomonas mendoza*, *Dermatococcus dermatoides*, *Denitrifying lipophilic bacteria*, *Xylose-oxidizing achromobacter*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcium acetate*, *Trichophyton mentagrophytes*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter krusei*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; mixing said compound or combination of compounds with the solution of said one or more inactivated proteins; and determining whether said compound or combination of compounds binds to said one or more inactivated proteins. In some embodiments, the method may further include, based on said determination, identifying the compound or combination of compounds that binds to said one or more inactivated proteins in vitro.

[0056] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas oryzae, Sphingosine vesiculosus, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiformis, Lactobacillus curvatureii, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvaticus (D), phylum The method comprises: *Pseudomonas dossa*, *Dermatococcus dermatoides*, *Denitrifying lipophilic bacteria*, *Xylose-oxidizing achromobacterium*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcareae*, *Trichomonas testis*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter krusei*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; introducing said one or more inactivated proteins into a mammalian inflammation model; introducing said compounds or combinations of said compounds into said mammalian inflammation model; and determining whether said compounds or combinations of said compounds reduce inflammatory activity in said model. In some embodiments, the method may further include, based on said determination, identifying compounds or combinations of said compounds that reduce the growth or population of said one or more cultures in vitro. In some implementations, the compound or combination of compounds may be one or more anti-inflammatory compounds.

[0057] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing ocular diseases, the method comprising: administering the compound or combination of compounds to a mammalian model described herein; and determining whether the compound or combination of compounds is effective in reducing or preventing one or more symptoms of the ocular disease. In some embodiments, the compound or combination of compounds is administered after drusen-like lesions have formed in the mammalian model. In some embodiments, the compound or combination of compounds is one or more compounds or combinations of compounds identified according to the in vitro screening methods described herein. In some embodiments, the injection may include intraocular injection. In some embodiments, the one or more symptoms are selected from the group consisting of the formation of drusen-like lesions, microbial growth or load, production of inflammatory molecules or markers, and combinations thereof.

[0058] The microorganisms used in the method can be substantially biopure species or a variety of different biological species. In some embodiments, the microorganisms include at least one species that is a cause of eye diseases. In some embodiments, the microorganisms include at least one species, wherein killing or inhibiting the growth of said at least one species is beneficial for treating or preventing eye diseases. The culturing of the microorganisms and the selection of the culture medium can be performed using any techniques known in the art, some exemplary details of which are shown in the Embodiments section. In some embodiments, the microorganisms can be cultured in a liquid cooked meat culture medium. There are no particular limitations on the methods for measuring or determining microbial growth, and they are generally known in the art; some exemplary methods are described herein in the Embodiments section. To avoid ambiguity, the measurement or determination of microbial growth herein does not require quantitative measurement. In some embodiments, visual observation may be sufficient, for example, when the test compound prevents visible growth of microorganisms at or below the maximum test concentration and / or when the test compound prevents visible colony formation of microorganisms at or below the maximum test concentration.

[0059] Candidate therapeutic agents can be identified using any suitable technique known in the art. In some embodiments, a test compound can be identified as a candidate therapeutic agent, for example, for the treatment or prevention of a corresponding eye disease, when it inhibits the growth of microorganisms compared to a control at or below the maximum test concentration. In some embodiments, a test compound can be identified as a candidate therapeutic agent when it prevents visible growth of microorganisms at or below the maximum test concentration. In some embodiments, a test compound can be identified as a candidate therapeutic agent when it prevents visible colony formation of microorganisms at or below the maximum test concentration.

[0060] Test compounds can be tested at a single concentration or at multiple concentrations. In some embodiments, a minimum inhibitory concentration (MIC) can also be established for the respective test compound, which allows for comparisons between different test compounds and aids in the further identification / selection of candidate therapeutics.

[0061] Screening methods for AMD

[0062] In some specific embodiments, screening methods can be used to identify candidate therapeutic agents for treating or preventing AMD. In any of the embodiments described herein, unless obviously contradicted by the context, AMD can be dry or wet age-related macular degeneration with drusenic symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerative drusen), such as dry or wet age-related macular degeneration with soft drusen symptoms. In some embodiments, the method includes: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; and b) measuring the growth of microorganisms in the culture medium in the presence of the test compound. Typically, microorganisms include species enriched in the intraocular spaces (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with AMD compared to a healthy subject. For example, in some embodiments, microorganisms include species enriched in the aqueous humor, vitreous fluid, and / or soft drusen of a subject with AMD compared to a healthy control. In some embodiments, the microorganisms may include one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophagium harzianum, Bacillus licheniformis, and Xanthomonas orientalis. In some embodiments, the microorganisms may include Bacillus megaterium and / or Pseudomonas putida. In some embodiments, the microorganisms include at least Bacillus megaterium. In some embodiments, the microorganisms may also be a substantially biopure population of Bacillus megaterium.

[0063] Different initial concentrations of microorganisms can be used in the screening method described herein. For example, in some embodiments, for the screening method described herein, a concentration of approximately 1*10⁻¹ μL to approximately 5001 μL (such as approximately 1001 μL) can be used. 5 Up to 1*10 9 (such as approximately 1*10) 6 Approximately 1*10 8 Or approximately 1*10 8 A suspension of *Bacillus megaterium* cells per mL is placed in a petri dish containing approximately 10-15 mL of culture medium and incubated for 24 hours at a suitable temperature and under suitable conditions, such as 37°C. For example, in some embodiments, for the screening method described herein, approximately 1 x 10⁻⁶ cells per culture can be used. 5 Up to 1*10 9 (For example, approximately 1*10) 5 Or 1*10 7 ) giant bacilli.

[0064] In some embodiments, the microorganisms may include a mixture of microbial species that are substantially similar to those observed in the aqueous humor, vitreous humor, and / or soft drusen of a subject with age-related macular degeneration (AMD). For example, in some embodiments, pathogenic species identified in the aqueous humor, vitreous humor, and / or soft drusen of a subject with AMD may be included in the microorganisms used in the screening method. The term "substantially similar" does not require that the microorganisms have the same composition of microbial species as those found in the aqueous humor, vitreous humor, and / or soft drusen of a subject with AMD. It is sufficient for the microorganisms to include a majority of the identified (preferably pathogenic) microbial species enriched in the aqueous humor, vitreous humor, and / or soft drusen of a subject with AMD, 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 microorganisms may be derived partly or entirely from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. In some implementations, when a test compound inhibits the growth of microorganisms (e.g., Bacillus megaterium) compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of AMD.

[0065] In some embodiments, the screening method for identifying candidate therapeutics for the treatment or prevention of AMD may also include a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with age-related macular degeneration (AMD) compared to a healthy subject; b) culturing a microorganism comprising at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganism in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganism compared to a control.

[0066] In some embodiments, the determination may be to obtain information that one or more microbial species are enriched in the intraocular space of a subject with AMD compared to a healthy subject. In some embodiments, the determination may be to assess the presence, absence, and / or quantity of microorganisms in samples from the intraocular space of a subject with AMD, and optionally to compare the presence, absence, and / or quantity of said microorganisms with a healthy control. Methods for assessing the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor, vitreous humor, and / or soft drusen of a subject with age-related macular degeneration. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. In some implementations, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of AMD.

[0067] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of AMD may also include: a) obtaining samples from the intraocular space of a subject with AMD, such as aqueous humor, vitreous fluid, and / or drusen; b) incubating the samples in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the samples are obtained from the aqueous humor of a subject with AMD. In some embodiments, the samples are obtained from the vitreous fluid of a subject with AMD. In some embodiments, the samples are obtained from drusen of a subject with AMD. As shown in the Examples section herein, incubation of the samples can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the samples from the subject. In some embodiments, a negative control may be used. In some embodiments, when a test compound inhibits the growth of microorganisms in a culture medium compared to a control, it can be identified as a candidate therapeutic for the treatment or prevention of AMD.

[0068] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing AMD, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects with AMD, family members or closely related subjects with AMD, or deceased subjects known to have AMD; culturing one or more organisms from the sample under conditions selected from those simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; adding the compound or combination of compounds to the one or more cultures; and determining whether the compound or combination of compounds reduces the growth of the one or more cultures or reduces their population size. In some embodiments, the method may further include, based on the determination, identifying compounds or combinations of compounds that reduce the growth of the one or more cultures or reduce their population size in vitro.

[0069] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas aeruginosa, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiformis, Lactobacillus curvatureii, Burkholderia polyphaga. The method involves adding the following compounds to one or more cultures: *Lactobacillus delbrueckii*, *Subthermia sylvatica* (D), *Pseudomonas mendoza*, *Dermatococcus dermatophytes*, *Denitrifying lipophilic bacteria*, *Xylose-oxidizing achromobacterium*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcium acetate*, *Trichophyton mentagrophytes*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter kurstii*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; adding the compounds or combinations thereof to the one or more cultures; and determining whether the compounds or combinations thereof reduce the growth or population of the one or more cultures. In some embodiments, the method may further include, based on the determination, identifying compounds or combinations thereof that reduce the growth or population of the one or more cultures in vitro.

[0070] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds in treating or preventing AMD, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects with AMD, family members or closely related subjects with AMD, or deceased subjects known to have AMD; culturing one or more organisms from the sample under conditions simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; mixing the compound or combination of compounds with the solution of the one or more inactivated proteins; and determining whether the compound or combination of compounds binds to the one or more inactivated proteins.

[0071] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds in treating or preventing AMD, the method comprising: obtaining a sample of aqueous humor or vitreous fluid from a subject selected from subjects with AMD, family members or closely related subjects with AMD, or deceased subjects known to have AMD; culturing one or more organisms from the sample under conditions selected from those simulating the intraocular space of a human eye or in a cooked meat culture medium to produce one or more cultures; obtaining a solution of one or more inactivated proteins derived from the one or more cultures; introducing the one or more inactivated proteins into a mammalian inflammation model; introducing the compound or combination of compounds into the mammalian inflammation model; and determining whether the compound or combination of compounds reduces inflammatory activity in the model.

[0072] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating or preventing eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas oryzae, Sphingosine vesiculosus, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiformis, Lactobacillus curvatureii, Burkholderia polyphaga, Lactobacillus delbrueckii, and Sylvatinus sylvatinus. The method comprises: *D. subtropical fever*, *Pseudomonas mendoza*, *Dermatococcus dermatoides*, *Denitrifying lipophilic bacteria*, *Xylose-oxidizing achromobacter*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcium acetate*, *Trichophyton mentagrophytes*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter krusei*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; mixing said compound or combination of compounds with the solution of said one or more inactivated proteins; and determining whether said compound or combination of compounds binds to said one or more inactivated proteins. In some embodiments, the method may further include, based on said determination, identifying the compound or combination of compounds that binds to said one or more inactivated proteins in vitro.

[0073] In some embodiments, the present invention provides a method for screening the efficacy of compounds or combinations of compounds in treating eye diseases, the method comprising: culturing one or more organisms to produce one or more cultures under conditions selected from those simulating the intraocular space of the human eye or in a cooked meat culture medium, wherein the one or more organisms are selected from the group consisting of: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, Xanthomonas aeruginosa, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia petrosiforme, Lactobacillus curvatureii, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvaticus (D), Mendoza The method comprises the following species: *Pseudomonas*, *Dermatococcus*, *Denitrifying Lipophilia*, *Xylose-oxidizing Achromobacter*, *Sphingosine japonicus*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebryophyte ebaceae*, *Acinetobacter baumannii*, *Acinetobacter calcareae*, *Trichomonas testis*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter krusei*, *Bacillus fermentum*, *Serratia marcescens*, *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Bacillus flavus*, and combinations thereof; obtaining a solution of one or more inactivated proteins derived from said one or more cultures; introducing said one or more inactivated proteins into a mammalian inflammation model; introducing said compounds or combinations of said compounds into said mammalian inflammation model; and determining whether said compounds or combinations of said compounds reduce inflammatory activity in said model. In some embodiments, the method may further include, based on said determination, identifying compounds or combinations of said compounds that reduce the growth or population of said one or more cultures in vitro. In some implementations, the compound or combination of compounds may be one or more anti-inflammatory compounds.

[0074] In some embodiments, the present invention provides a method for screening the efficacy of a compound or combination of compounds in treating an ocular disease, the method comprising: administering the compound or combination of compounds to a mammalian model described herein; and determining whether the compound or combination of compounds is effective in reducing or preventing one or more symptoms of AMD. In some embodiments, the compound or combination of compounds is administered after drusen-like lesions have formed in the mammalian model. In some embodiments, the compound or combination of compounds is one or more compounds or combinations of compounds identified according to the in vitro screening methods described herein. In some embodiments, administration may include intraocular injection. In some embodiments, the one or more symptoms are selected from the group consisting of drusen-like lesion formation, microbial growth or load, production of inflammatory molecules or markers, and combinations thereof.

[0075] Screening methods for other diseases

[0076] In some embodiments, screening methods can be used to identify candidate therapeutic agents for treating or preventing BD. In some embodiments, the method includes: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; and b) measuring the growth of microorganisms in the culture medium in the presence of the test compound, wherein the microorganisms include species enriched in the intraocular spaces (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with BD compared to a healthy subject. For example, in some embodiments, the microorganisms include species enriched in the aqueous humor and / or vitreous fluid of a subject with BD compared to a healthy control. In some embodiments, the microorganisms may include one or more species selected from: *Sphingomonas vesicatoria*, *Klebsiella pneumoniae*, *Pseudomonas fluorescens*, *Rolstonia pinnatifida*, *Lactobacillus curvatureii*, *Burkholderia polyphaga*, *Lactobacillus delbrueckii*, and *Subthermia sildenafil* (D). In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with BD. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with BD. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with BD. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of BD.

[0077] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of BD may also include a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with BD compared to a healthy subject; b) culturing microorganisms including at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may be obtaining information that one or more microbial species are enriched in the intraocular space of a subject with BD compared to a healthy subject. In some embodiments, the determination may be assessing the presence, absence, and / or amount of microorganisms in samples from the intraocular space of a subject with BD, and optionally comparing the presence, absence, and / or amount of the microorganisms to a healthy control. Methods for assessing the presence, absence, and / or amount of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with BD. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with BD. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with BD. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of BD.

[0078] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of BD may also include: a) obtaining a sample of the intraocular space, such as aqueous humor and / or vitreous fluid, from a subject with BD; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying a candidate therapeutic that inhibits the growth of the microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with BD. In some embodiments, the sample is obtained from the vitreous fluid of a subject with BD. As shown in the Examples section herein, incubation of the sample can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, when the test compound inhibits the growth of microorganisms in the culture medium compared to a control, it can be identified as a candidate therapeutic for the treatment or prevention of BD.

[0079] In some embodiments, screening methods can be used to identify candidate therapeutic agents for the treatment or prevention of cataracts. In some embodiments, the method includes: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; and b) measuring the growth of microorganisms in the culture medium in the presence of the test compound, wherein the microorganisms include species enriched in the intraocular spaces (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with cataracts compared to a healthy subject. For example, in some embodiments, the microorganisms include species enriched in the aqueous humor and / or vitreous fluid of a subject with cataracts compared to a healthy control. In some embodiments, the microorganisms may include one or more species selected from: *Pseudomonas mendoza*, *Dermatococcus spp.*, *Denitrifying lipophilic bacteria*, *Achromobacter xylose oxidizing bacteria*, *Sphingosporium japonicum*, *Mycobacterium abscessum*, *Arthrobacter aureum*, *Prevotella dentata*, *Rhizobium sinense*, and *Ebrionella eczemae*. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with cataracts. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of cataracts.

[0080] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of cataracts may also include a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with cataracts compared to a healthy subject; b) culturing microorganisms including at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may be obtaining information that one or more microbial species are enriched in the intraocular space of a subject with cataracts compared to a healthy subject. In some embodiments, the determination may be assessing the presence, absence, and / or quantity of microorganisms in samples from the intraocular space of a subject with cataracts, and optionally comparing the presence, absence, and / or quantity of the microorganisms to a healthy control. Methods for assessing the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with cataracts. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with cataracts. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of cataracts.

[0081] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of cataracts may also include: a) obtaining a sample of the intraocular space, such as aqueous humor and / or vitreous fluid, from a subject with cataracts; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying a candidate therapeutic that inhibits the growth of the microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with cataracts. In some embodiments, the sample is obtained from the vitreous fluid of a subject with cataracts. As shown in the Examples section herein, incubation of the sample can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, when the test compound inhibits the growth of microorganisms in the culture medium compared to a control, it can be identified as a candidate therapeutic for the treatment or prevention of cataracts.

[0082] In some embodiments, screening methods can be used to identify candidate therapeutic agents for treating or preventing GLA. In some embodiments, the method includes: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; and b) measuring the growth of microorganisms in the culture medium in the presence of the test compound, wherein the microorganisms include species enriched in the intraocular spaces (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with GLA compared to a healthy subject. For example, in some embodiments, the microorganisms include species enriched in the aqueous humor and / or vitreous fluid of a subject with GLA compared to a healthy control. In some embodiments, the microorganisms may include one or more species selected from: Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter krusei, fermenting paired bacilli, and Serratia marcescens. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed in the aqueous humor and / or vitreous fluid of a subject with GLA. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with GLA. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with GLA. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of GLA.

[0083] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of GLA may also include a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with GLA compared to a healthy subject; b) culturing microorganisms including at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may be obtaining information that one or more microbial species are enriched in the intraocular space of a subject with GLA compared to a healthy subject. In some embodiments, the determination may be assessing the presence, absence, and / or quantity of microorganisms in samples from the intraocular space of a subject with GLA, and optionally comparing the presence, absence, and / or quantity of the microorganisms to a healthy control. Methods for assessing the presence, absence, and / or quantity of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed in the aqueous humor and / or vitreous fluid of a subject with GLA. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with GLA. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with GLA. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of GLA.

[0084] In some embodiments, a screening method for identifying candidate therapeutic agents for the treatment or prevention of GLA may also include: a) obtaining a sample of the intraocular space, such as aqueous humor and / or vitreous fluid, from a subject with GLA; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying a candidate therapeutic agent that inhibits the growth of the microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with GLA. In some embodiments, the sample is obtained from the vitreous fluid of a subject with GLA. As shown in the Examples section herein, incubation of the sample can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, when the test compound inhibits the growth of microorganisms in the culture medium compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of GLA.

[0085] In some embodiments, screening methods can be used to identify candidate therapeutic agents for treating or preventing VKH. In some embodiments, the method includes: a) culturing microorganisms in a suitable culture medium in the presence of a test compound; and b) measuring the growth of microorganisms in the culture medium in the presence of the test compound, wherein the microorganisms include species enriched in the intraocular spaces (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with VKH compared to a healthy subject. For example, in some embodiments, the microorganisms include species enriched in the aqueous humor and / or vitreous fluid of a subject with VKH compared to a healthy control. In some embodiments, the microorganisms may include one or more species selected from: *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium aureum*, and *Goldobacter davidii*. In some embodiments, the microorganisms may include a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with VKH. In some embodiments, the microorganisms may be derived, in whole or in part, from the aqueous humor and / or vitreous fluid of a subject with VKH. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with VKH. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it may be identified as a candidate therapeutic agent for the treatment or prevention of VKH.

[0086] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of VKH may also include a) identifying, or having identified, one or more microbial species enriched in the intraocular space of a subject with VKH compared to a healthy subject; b) culturing microorganisms including at least one of the enriched microbial species in a suitable culture medium in the presence of a test compound; c) measuring the growth of the microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying candidate therapeutics that inhibit the growth of the microorganisms compared to a control. In some embodiments, the determination may be obtaining information that one or more microbial species are enriched in the intraocular space of a subject with VKH compared to a healthy subject. In some embodiments, the determination may be assessing the presence, absence, and / or amount of microorganisms in samples from the intraocular space of a subject with VKH, and optionally comparing the presence, absence, and / or amount of the microorganisms to a healthy control. Methods for assessing the presence, absence, and / or amount of microorganisms include those described in PCT application number PCT / CN2018 / 112022. In some embodiments, the microorganisms may comprise a mixture of microbial species substantially similar to those observed from the aqueous humor and / or vitreous fluid of a subject with VKH. In some embodiments, the microorganisms may be derived partially or entirely from the aqueous humor and / or vitreous fluid of a subject with VKH. For example, in some embodiments, the microorganisms may be obtained by culturing samples obtained from the aqueous humor and / or vitreous fluid of a subject with VKH. In some embodiments, when a test compound inhibits the growth of microorganisms compared to a control, it can be identified as a candidate therapeutic agent for the treatment or prevention of VKH.

[0087] In some embodiments, screening methods for identifying candidate therapeutics for the treatment or prevention of VKH may also include: a) obtaining a sample of the intraocular space, such as aqueous humor and / or vitreous fluid, from a subject with VKH; b) incubating the sample in a culture medium in the presence of a test compound; c) measuring the growth of microorganisms in the culture medium in the presence of the test compound; and optionally d) identifying a candidate therapeutic that inhibits the growth of the microorganisms compared to a control. In some embodiments, the sample is obtained from the aqueous humor of a subject with VKH. In some embodiments, the sample is obtained from the vitreous fluid of a subject with VKH. As shown in the Examples section herein, incubation of the sample can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the sample from the subject. In some embodiments, a negative control may be used. In some embodiments, when the test compound inhibits the growth of microorganisms in the culture medium compared to a control, it can be identified as a candidate therapeutic for the treatment or prevention of VKH.

[0088] Test compounds

[0089] There are no particular limitations on the test compounds used in the screening methods described herein (e.g., for identifying candidate therapeutics or preventative agents for AMD). For example, the test compound can be a small molecule, a biological product (including peptides and polynucleotides), or a conjugate of a small molecule and a biological product, such as an antibody-drug conjugate. Other suitable categories of test compounds can also be screened using the methods described herein. The test compound does not have to be a single compound. In some cases, mixtures of compounds can be used for screening. For example, in some embodiments, extracts or fractions thereof, such as traditional Chinese medicine (TCM) extracts, can be used as test compounds for screening.

[0090] For example, the test compound can be a small molecule drug, a chemical drug, a macromolecule drug, a biological drug, or a natural drug (traditional Chinese medicine or its extract). In some embodiments, the test compound may include β-lactam antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, chloramphenicol antibiotics, macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics, rifamycin antibiotics, echinocandins, polyene antibiotics, pyrimidine antibiotics, allylamine antibiotics, or azole antibiotics, or combinations thereof.

[0091] In some embodiments, the test compound may include one or more of the following: β-lactam antibiotics, including penicillins, cephalosporins, thiazides, monolactamases, β-lactamase inhibitors, methicillins, etc.; aminoglycoside antibiotics, including streptomycin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribostamycin, azithromycin, etc.; tetracycline antibiotics, including tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; chloramphenicol antibiotics, including chloramphenicol, thiamphenicol, etc.; macrolide antibiotics, including erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, and midecamycin. Antibiotics include: cyclophosphamide, josamycin, azithromycin, etc.; glycopeptide antibiotics, including vancomycin, teicoplanin, etc.; quinolone antibiotics, including norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin; nitroimidazole antibiotics, including metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics, including rifampin; echinocandins; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics: fosfomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, etc.

[0092] In some embodiments, the test compound may include one or more of the following: insect antimicrobial peptides, such as Lepidoptera antimicrobial peptides, Diptera antimicrobial peptides, Coleoptera antimicrobial peptides, Odonata antimicrobial peptides, Hymenoptera antimicrobial peptides, silkworm antimicrobial peptides, etc.; mammalian antimicrobial peptides, such as porcine antimicrobial peptides, sheep antimicrobial peptides, bovine antimicrobial peptides, human antimicrobial peptides, etc.; amphibian antimicrobial peptides: African clawed frog, etc.; antimicrobial peptides from fish, mollusks, and crustaceans: leopard sole (pardachirus pavoninus) antimicrobial peptides, catfish (parasilurus asotus) antimicrobial peptides, mussel antimicrobial peptides, shrimp antimicrobial peptides, etc.; plant antimicrobial peptides: thionin, etc.; bacterial antimicrobial peptides: bacitracin, brevicin, polymyxin, and nisin.

[0093] In some embodiments, the test compound may include one or more of the following extracts or fractions: calcined ancient ink, Salvia Miltiorrhiza, Arnebia euchroma, Radix Isatidis, Houttuynia, Honeysuckle, Rhizoma Coptis, Scutellaria, Dandelion, Purslane, Hawthorn, Isatidis Folium, Forsythia, Herba Artemisiae Capillaris, Andrographis Paniculata Nees, Radix Bupleuri, Rhubarb, and Euphorbia Humifusa, Stemonae, Garlic, Cortex Phellodendri, Eucommia, Cortex Fraxini, Fructus Cnidii, Galla Chinensis, Viola yedoensis makino, Fructus Mume, Radix Glycyrrhizae, Pericarpium Granati, Schisandra chinensis, Spina Gleditsiae, Terminalia Chebula, Sophora flavescens, Cortex Pseudolaricis, Epimedium, Artemisia apiacea Hance.

[0094] The screening methods described above can be low-, medium-, or high-throughput screening methods, and typically can screen multiple test compounds. For example, in some embodiments, the screening method can screen more than one test compound in parallel (including substantially simultaneous tests), such as screening more than 10, 100, or 1000 compounds in parallel. Test compounds can be tested at a single concentration or at multiple concentrations. In some embodiments, when screening multiple test compounds, the multiple test compounds include at least one test compound that is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. In some embodiments, the multiple test compounds include at least one test compound that is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline. In some embodiments, the test compound is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of the microorganism. For example, in some embodiments, the test compound is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline.

[0095] In some embodiments, the test compound may include an anti-inflammatory compound. Suitable anti-inflammatory compounds may include ophthalmic compounds known in the art. In some embodiments, the anti-inflammatory compound may include steroidal or non-steroidal anti-inflammatory compounds, plant extracts or fractions of extracts, or combinations thereof.

[0096] animal models

[0097] In various embodiments, the present invention also provides an animal model for eye diseases and a method for making the animal model.

[0098] In some embodiments, the present invention provides a method for creating an animal model, the method comprising introducing microorganisms and / or inactivated proteins from said microorganisms into the intraocular space of an animal eye. Typically, the microorganisms include species enriched in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject suffering from an eye disease compared to a healthy subject, wherein the eye disease is selected from cataract (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), endophthalmitis (EOS), and combinations thereof, and the introduction causes one or more symptoms of the eye disease. In some implementations, the method further includes identifying or having identified one or more microbial species enriched in the intraocular space of a subject with an eye disease compared to a healthy subject, wherein the eye disease is selected from age-related macular degeneration (AMD), Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof.

[0099] In some embodiments, the method may introduce live microorganisms into the intraocular space of an animal's eye. In some embodiments, the method may introduce inactivated proteins of the microorganisms, such as ultrasound-inactivated proteins derived from microorganisms, into the intraocular space of an animal's eye. The subject and animal mentioned in the methods herein may be the same or different. For example, in some embodiments, when the eye disease is a disease of a pet animal, the subject and animal may be the same. In some embodiments, the eye 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., a monkey). In some embodiments, the animal has an ocular anatomy and / or intraocular environment similar to that of a human. Preferably, the animal does not have an eye disease prior to the introduction of the microorganisms and / or inactivated proteins derived from said microorganisms.

[0100] AMD Animal Models

[0101] In some specific embodiments, the present invention provides a method for creating an animal model of AMD. In some embodiments, the method includes introducing microorganisms and / or inactivated proteins from said microorganisms into the intraocular space of an animal eye. Typically, the microorganisms include species enriched in the intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous fluid in the posterior chamber, retina, choroid, optic nerve, lens, or iris) of a subject with AMD compared to a healthy subject, and the introduction causes one or more symptoms of AMD. Unless the context otherwise requires, the microorganisms introduced into the intraocular space of an animal should refer to live microorganisms. In some embodiments, the microorganisms include one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophalophoribacterium harzianum, Bacillus licheniformis, and Xanthomonas orientalis. 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 are a substantially biopure population of *Bacillus megaterium*. In some embodiments, the microorganisms comprise a mixture of microbial species substantially similar to those observed from the aqueous humor, vitreous humor, and / or soft drusen of a subject with age-related macular degeneration. In some embodiments, the microorganisms are derived partially or entirely from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. For example, in some embodiments, the microorganisms can be obtained by culturing samples obtained from the aqueous humor and / or vitreous humor of a subject with age-related macular degeneration. Preferably, the animal is a non-human mammal, more preferably a non-human primate (e.g., a monkey). In some embodiments, the animal has an ocular anatomy and / or intraocular environment similar to that of a human. In some embodiments, the animal is a rhesus macaque, such as a cynomolgus monkey. In some embodiments, the animal is not a rhesus macaque. In some embodiments, the animal is not a cynomolgus monkey.

[0102] Microorganisms and / or inactivated proteins derived from said microorganisms can be introduced into any suitable intraocular space of an animal. In some embodiments, microorganisms and / or inactivated proteins derived from said microorganisms are injected into the subretinal space of the animal. Although it is common practice to inject microorganisms and / or inactivated proteins derived from said microorganisms into the eye of an animal, other delivery methods are also suitable.

[0103] Typically, microorganisms and / or inactivated proteins from said microorganisms are introduced in amounts and concentrations sufficient to cause one or more symptoms of AMD. For example, as shown in the Examples section, 20 CFU of bacteria in about 20 μL of PBS solution can cause one or more symptoms of AMD, such as drusen-like lesions. In some embodiments, microorganisms and / or inactivated proteins from said microorganisms are introduced in amounts and concentrations sufficient to cause: 1) drusen-like lesions, for example, in the retinal tissue of an animal; 2) drusen-like nodules, for example, beneath the retinal pigment epithelium in the eye of an animal; 3) pyroptosis of retinal pigment epithelial cells, for example, in the eye of an animal; 4) activation and / or inflammation of the complement system in the eye of an animal, for example, increased expression of proteins such as C5A, CFH, caspase 1, and NLRP3; 5) secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of an animal; or 6) any combination of 1)-5).

[0104] The animals used in the methods for creating the animal models described herein are preferably healthy animals, for example, those without eye disease prior to the introduction of the microorganisms and / or inactivated proteins from said microorganisms. Preferably, no antibiotics are administered to the animals before and during the introduction of the microorganisms and / or proteins from said microorganisms, for example, before the appearance of one or more symptoms of AMD.

[0105] In some embodiments, a method for creating an animal model of AMD may include introducing a sample from a subject suffering from AMD into the intraocular space of the animal's eye, wherein the sample is obtained from the subject's intraocular space, and wherein the introduction causes one or more symptoms of AMD. In some embodiments, the sample is incubated in a culture medium and optionally purified and / or formulated for injection prior to introduction into the animal. In some embodiments, the method further includes 1) obtaining a sample, such as aqueous humor, vitreous fluid, and / or soft drusen, from the subject's intraocular space; and 2) incubating the sample in a culture medium. In some embodiments, the sample is obtained from the aqueous humor of a subject suffering from AMD. In some embodiments, the sample is obtained from the vitreous fluid of a subject suffering from AMD. In some embodiments, the sample is obtained from soft drusen of a subject suffering from AMD. As shown in the Examples section herein, incubation of the sample can typically be performed in a sterile culture medium in a sterile environment (such as a sealed environment) to avoid introducing microbial species that were not initially present in the sample from the subject.

[0106] Typically, methods for creating AMD animal models can induce one or more AMD symptoms in animals that persist for a period of time. For example, without intervention, animal models created by the methods described herein typically exhibit one or more AMD symptoms over a period longer than one week, one month, or throughout the animal's lifespan. The animal models created by the methods described herein are also a novel feature of embodiments of the present invention.

[0107] The AMD animal models described herein can also be used to identify candidate therapeutics for the treatment or prevention of AMD. For example, in some embodiments, the invention also provides a screening method comprising a) administering a test compound to an AMD animal model as described herein; b) determining the severity of one or more symptoms of the eye disease after administration; and optionally c) identifying candidate therapeutics that reduce at least one of the symptoms compared to a control. In some embodiments, when compared to a control, administration of the test compound 1) reduces, for example, drusen-like lesions in the retinal tissue of an animal; 2) reduces, for example, drusen-like nodules beneath the retinal pigment epithelium in the animal eye; 3) reduces pyroptosis of retinal pigment epithelial cells in the animal eye; 4) reduces activation and / or inflammation of the complement system in the animal eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reduces the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the animal eye; or 6) any combination of 1)-5), and such a test compound may be identified as a candidate therapeutic for the treatment or prevention of AMD. In some embodiments, when compared to a control, administration of the test compound kills or inhibits the growth of microorganisms in the eyes (e.g., intraocular spaces or cavities), blood, and / or gastrointestinal tract, such as the gut, in animal models, and such test compounds may also be identified as candidate therapeutics for the treatment or prevention of AMD. In some embodiments, the relevant information for the "control" may be information observed from animals prior to administration of the test compound. In some embodiments, the relevant information for the "control" may be information observed from animals receiving placebo treatment, such as administration of a placebo formulation without the test compound.

[0108] There are no limitations on the test compounds used for screening methods in animal models of AMD (as described herein), but preferably, the test compounds are pre-screened (e.g., using any screening method described herein) to be effective in killing or inhibiting the growth of microorganisms (e.g., Bacillus megaterium) that accumulate in the intraocular space of subjects with AMD compared to healthy controls. Test compounds can also be administered via any suitable route, at any test dosing regimen, and at any suitable test dose, which can be selected by those skilled in the art based on factors such as the potency of the test compound (if known). For example, test compounds can be administered orally, topically, intravitreally, intramuscularly, subcutaneously, or intravenously.

[0109] Screening methods using AMD animal models (as described herein) are typically low- to medium-throughput screening methods. In some embodiments, multiple test compounds are screened, and said multiple test compounds include at least one test compound that is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of said microorganisms. In some embodiments, said multiple test compounds include at least one test compound that is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline. In some embodiments, the test compound is not a known broad-spectrum antibiotic or a known antibiotic effective against one or more species of said microorganisms. For example, in some embodiments, the test compound is not ampicillin, vancomycin, neomycin, metronidazole, or tetracycline.

[0110] In some embodiments, the present invention provides a method for generating a mammalian model of an eye disease, the method comprising: introducing one or more microorganisms and / or one or more inactivated proteins of said one or more microorganisms into the eye of a mammal, thereby generating a mammalian model. In some embodiments, the method may further include monitoring the development and progression of one or more biomarkers of the eye disease. Biomarkers of the eye disease may include those biological and / or chemical biomarkers known in the art for a given disease, and may include, but are not limited to, symptoms of the eye disease. In some embodiments, monitoring the development and progression of one or more biomarkers of the eye disease may include monitoring ocular inflammatory responses in the mammal. In some embodiments, monitoring the development and progression of one or more biomarkers of the eye disease may include monitoring the formation or progression of drusen-like lesions. In some embodiments, the method may further include allowing sufficient time for the mammal to develop drusen-like lesions after the introduction of said one or more microorganisms and / or one or more inactivated proteins of said one or more microorganisms. In some embodiments, the introduction of said one or more microorganisms and / or one or more inactivated proteins of said one or more microorganisms may include intraocular injection of said one or more microorganisms or one or more inactivated proteins of said one or more microorganisms. In some embodiments, intraocular injection may include injection into the vitreous fluid or aqueous humor of the mammal.

[0111] Treatment

[0112] In some embodiments, the present invention also provides methods for treating or preventing AMD. In some embodiments, the method includes administering to a subject in need an effective amount of any candidate therapeutic agent for AMD identified in any screening method herein. In some embodiments, the method includes: identifying or having identified a subject infected, for example, in the intraocular space with one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophalocele, Bacillus licheniformis, and Xanthomonas aeruginosa; and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified in any screening method herein. In some embodiments, the method includes identifying or having identified a subject infected, for example, in the intraocular space with Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium; and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified in any screening method herein. In some embodiments, the method includes: selecting a subject infected in the intraocular space with one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophyton harzianum, Bacillus licheniformis, and Xanthomonas aeruginosa; and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified in any of the screening methods herein. In some embodiments, the method includes selecting a subject infected in the intraocular space with, for example, Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium; and administering to the subject an effective amount of any candidate therapeutic agent for AMD identified in any of the screening methods herein. In some embodiments, the subject does not have Behcet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the subject has AMD. In some embodiments, the subject has not been diagnosed with AMD. In some embodiments, the subject is at risk of developing AMD. Administration is not limited to any particular route; for example, it can be oral, topical, intravitreal, intramuscular, subcutaneous, and / or intravenous.

[0113] In some embodiments, methods for treating or preventing AMD include: identifying or having identified a subject infected, for example, in the intraocular space with one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, and Xanthomonas aeruginosa; and administering an effective amount of antibiotic to said subject. As used herein, antibiotics refer to compounds with antibacterial activity, which may be naturally occurring or synthetic. Examples of antibiotics are provided herein. In some embodiments, the method includes identifying or having identified a subject infected, for example, in the intraocular space with Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium; and administering an effective amount of antibiotic to the subject. In some embodiments, the method includes selecting a subject infected in the intraocular space with one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophyton harzianum, Bacillus licheniformis, and Xanthomonas aeruginosa, and administering an effective amount of antibiotic to the subject. In some embodiments, the method includes selecting a subject infected in the intraocular space with, for example, Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium, and administering an effective amount of antibiotic to the subject. In some embodiments, the method includes selecting a subject infected in the intraocular space with, for example, Bacillus megaterium, and administering an effective amount of antibiotic to the subject. In some embodiments, the subject does not have Behcet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the subject has AMD. In some embodiments, the subject has not been diagnosed with AMD. In some embodiments, the subject is at risk of developing AMD. Administration is not limited to any particular route; for example, it can be oral, topical, intravitreal, intramuscular, subcutaneous, and / or intravenous. In any embodiment herein, an "effective amount" of antibiotic can be an amount that effectively kills or inhibits the growth of one or more microbial species in the eye of the treated subject, wherein said one or more microbial species are enriched in AMD patients compared to healthy controls; for example, said one or more microbial species can be Bacillus megaterium and / or Pseudomonas putida, preferably at least Bacillus megaterium.

[0114] In some embodiments, the present invention also provides methods for achieving the following in subjects in need: 1) reducing drusen-like lesions, for example, on retinal tissue; 2) reducing drusen-like nodules, for example, beneath the retinal pigment epithelium in the eye; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing activation and / or inflammation of the complement system in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5), the method comprising administering to the subject an effective amount of any candidate therapeutic agent against AMD identified in any screening method herein. In some embodiments, the present invention also provides a method for treating drusen symptoms (e.g., soft drusen) in subjects in need, the method comprising administering to the subject an effective amount of any candidate therapeutic agent against AMD identified in any screening method herein. Drusen symptoms (e.g., soft drusen) can be caused by microbial infection such as by pathogens described herein. Symptoms of drusen (e.g., soft drusen) can be associated with subjects who have AMD.

[0115] In some embodiments, the present invention also provides methods for achieving the following in a subject in need: 1) reducing drusen-like lesions, for example, on retinal tissue; 2) reducing drusen-like nodules, for example, beneath the retinal pigment epithelium in the eye; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing activation and / or inflammation of the complement system in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5), wherein the method comprises administering an effective amount of antibiotic to the subject. For example, in some embodiments, the method is used to reduce drusen-like lesions in a subject. In some embodiments, the method is used to reduce drusen-like nodules in a subject. In some embodiments, the method is used to reduce pyroptosis of retinal pigment epithelial cells in the eye of a subject. In some embodiments, the method is used to reduce activation and / or inflammation of the complement system in the eye of a subject. In some embodiments, the method is used to reduce the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of a subject. Without being bound by theory, it is believed that antibiotics can kill or inhibit the growth of bacteria (e.g., pathogenic bacteria) in, for example, the intraocular space of a subject's eye, and thus reduce drusen formation, drusenoid lesions, and / or drusenoid nodules in subjects with AMD, which this document demonstrates is associated with infection by one or more pathogenic microorganisms (e.g., Bacillus megaterium and / or Pseudomonas putida). Pathogenic microorganisms, such as those described herein, such as Bacillus megaterium and / or Pseudomonas putida, are also considered to cause inflammation of the eye. Therefore, antibiotics administered that can kill or inhibit the growth of pathogenic microorganisms can also alleviate eye inflammation in subjects (e.g., subjects with AMD). In some embodiments, the invention also provides a method for treating drusen symptoms (e.g., soft drusen) in a subject in need, the method comprising administering an effective amount of antibiotic to the subject. Drusen symptoms (e.g., soft drusen) can be caused by microbial infection such as by pathogenic bacteria described herein. Symptoms of drusen (e.g., soft drusen) can be associated with subjects suffering from AMD. In some implementations, this method reduces drusen-like lesions and / or nodules.

[0116] In some embodiments, the present invention also provides methods for achieving the following in subjects in need: 1) reducing, for example, drusen-like lesions on retinal tissue; 2) reducing, for example, drusen-like nodules beneath the retinal pigment epithelium in the eye; 3) reducing pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing activation and / or inflammation of the complement system in the eye, for example, by reducing the expression of C5A, CFH, caspase 1, and NLRP3 proteins; 5) reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye; or 6) any combination of 1)-5), the method comprising administering to the subject an effective amount of the disclosed compound (e.g., Formula I (e.g., Formula I-1, Formula I-2, ...). Compounds of formulas I-3, I-4, I-5, II (e.g., formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10), III (e.g., formulas III-1, III-2, III-3), IV-1 or IV-2 (e.g., formulas IV-3, IV-4, IV-5, IV-6), glycosides (e.g., formula V), compounds selected from compounds 1-8, or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions comprising said compounds or pharmaceutically acceptable salts or esters thereof, wherein the aglycone of the glycoside is a phenolic compound, flavonoid, coumarin, benzoic acid, or sterol. For example, in some embodiments, the method is used to reduce drusen-like lesions in a subject. In some embodiments, the method is used to reduce drusen-like nodules in a subject. In some embodiments, the method is used to reduce pyroptosis of retinal pigment epithelial cells in the eye of a subject. In some embodiments, the method is used to reduce the activation and / or inflammation of the complement system in the eye of a subject. In some embodiments, the method is used to reduce the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells in the eye of a subject. Without wishing to be bound by theory, it is believed that the compounds of this disclosure can kill or inhibit the growth of bacteria (e.g., pathogenic bacteria) in, for example, the intraocular space of a subject's eye, and thus reduce drusen formation, drusenoid lesions, and / or drusenoid nodules in subjects with AMD, which this document demonstrates is associated with infection by one or more pathogenic microorganisms (e.g., Bacillus megaterium and / or Pseudomonas putida). Pathogenic microorganisms, such as those described herein, such as Bacillus megaterium and / or Pseudomonas putida, are also considered to cause inflammation of the eye. Therefore, the applied compounds of this disclosure, which can kill or inhibit the growth of pathogenic microorganisms, can also alleviate eye inflammation in subjects (e.g., subjects with AMD). In some embodiments, the present invention also provides a method for treating symptoms of drusen (e.g., soft drusen) in a subject in need, the method comprising administering an effective amount of the disclosed compound to the subject.Symptoms of drusen (e.g., soft drusen) can be caused by microbial infections such as those described herein. Symptoms of drusen (e.g., soft drusen) can be associated with subjects suffering from AMD. In some embodiments, this method reduces drusen-like lesions and / or nodules.

[0117] There are no particular limitations on the subjects suitable for treatment by the methods described herein. In some preferred embodiments, the subject has AMD. In some embodiments, AMD can be dry or wet age-related macular degeneration with drusenic symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerating drusen), such as dry or wet age-related macular degeneration with soft drusenic symptoms. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject has soft drusen deposited between the retinal pigment epithelium (RPE) and Bruch's membrane. In some embodiments, the subject has retinal pigment changes in the macula. In some embodiments, the subject has dry AMD. In some embodiments, the subject has wet AMD. In some embodiments, the subject is a human subject. In some embodiments, the subject is infected in the intraocular space with one or more species that are enriched in the intraocular space of AMD patients compared to healthy subjects, for example, as described herein. In some embodiments, the subject is infected in the intraocular space with one or more species selected from the following: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophyton harzianum, Bacillus licheniformis, and Xanthomonas aeruginosa. In some embodiments, the subject is infected in the intraocular space with Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium. In some embodiments, the subject does not have Behçet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any combination thereof. In some embodiments, the method may further include identifying, or having identified, the subject being infected in the intraocular space with one or more species enriched in the intraocular space of AMD patients compared to healthy subjects, for example, as described herein. In some embodiments, the method may further include identifying or having identified that the subject is infected in the intraocular space with one or more species selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophyton harzianum, Bacillus licheniformis, and Xanthomonas aeruginosa. In some embodiments, the method may further include identifying or having identified that the subject is infected in the intraocular space with Bacillus megaterium and / or Pseudomonas putida, preferably with at least Bacillus megaterium.

[0118] The administration of antibiotics is not limited to any particular route of administration. For example, administration can be oral, topical, intravitreal, intramuscular, subcutaneous, and / or intravenous. For example, in some embodiments, antibiotics are administered via intravitreal injection, such as intravitreal reservoir injection or intravitreal implantation. In some embodiments, a combination of two or more routes of administration (e.g., oral and intravitreal routes) can be used. For example, in some embodiments, antibiotics can be administered orally and intravitreal simultaneously or in any order. For example, in some embodiments, antibiotics can be administered orally and intravenously simultaneously or in any order. Other routes of administration may also be used in combination for the same active ingredient or two different active ingredients. Antibiotics can be formulated as solids, liquids, semi-solids, solutions, suspensions, implants, or any other suitable form. For example, oral antibiotics are typically in solid or liquid form. In some embodiments, antibiotics can be formulated as implants. When intravitreal injection is performed, there are no particular limitations on the injection site. For example, in some embodiments, the injection can be a suprachoroidal injection. Other suitable sites are known in the art. The effective dose can vary depending on a variety of factors, such as the time of administration, route of administration, duration of treatment, the potency of the antibiotic (e.g., for killing or inhibiting the growth of one or more microorganisms enriched in the intraocular space compared to healthy controls), its clearance rate, and whether another drug is administered concurrently. A variety of antibiotics can be used in the methods described herein, such as any of the antibiotics described herein, and any of the antibiotics described in PCT / CN2019 / 070572 filed January 7, 2019, the entire contents of which are incorporated herein by reference.

[0119] In some implementations, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or a azole antibiotic, or a combination thereof.

[0120] In some implementations, the antibiotic may include one or more of the following: β-lactam antibiotics, including penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacancillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pimecrolimus, pimecrolimus, ticarcillin; cephalosporins such as cefetrazol, cefadroxil, cefalexin, cefotaxime, cefotaxime, cefepime, cefepime, cefazolin, ceftriaxone, cefotaxime, cefoxitin, cefotaxime, cefotaxime, cefotaxime, cefotaxime, cefotaxime, cefotiam ... Cefuroxime, cefoxitin, cefprozil, cefuroxime, cefazolin, cefcarpine, cefodamide, cefdinir, ceftoran, cefotaxime, cefixime, cefotaxime, cefodizine, cefotaxime, cefimidazole, cefpodoxime, cefterenol, cefbuprofen, ceftiofur, cefotaxime, ceftriaxone, cefoperazone, ceftazidime, cefepime, cefrenaline, ceftiofur, cefazolin, cefepime, cefepime, ceftriaxone, cefoperazone, cefazolin, cefclorin, cefchlorazine, cefolomide, cefperazine, cefcarne, cefdrolone, cefpyridone, ceftriazole, cefvetril, cefmatine (cefmatilen), cefchlorammonium (cefme) The following antibiotics are listed: pidium, cefotaxime, cefoxitin, cefotaxime, cefoxitin, cefotaxime, thiamethoxam, monolactamase inhibitors, β-lactamase inhibitors, methicillins; aminoglycoside antibiotics, including streptomycin, gentamicin, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribosomycin, simvastatin, azithromycin, dibekacin, sisomicin, netilmicin, paromomycin, brevicone, etc.; tetracycline antibiotics, including tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; chloramphenicol antibiotics, including chloramphenicol, thiamphenicol, etc.; macrolide antibiotics. Antibiotics include: erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, midecamycin, josamycin, azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, etc.; glycopeptide antibiotics, including vancomycin, teicoplanin, etc.; quinolone antibiotics, including norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, including metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics, including rifampin; echinocandins; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; and azole antibiotics.Other antibiotics: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymyxin B combinations such as polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / bacitracin, etc.

[0121] In some implementation schemes, the antibiotic may be selected from amikacin, amoxicillin, ampicillin, arsenamine, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalosporin, cefalothin, cefamandole, cefazolin, cefdinir, ceftoranol, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, cefbufenozide, cefuroxime, chloramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dapoxetine, dapsone, dapoxetine, dicloxacillin, erythromycin, and doripenem. Doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, clocabimethionine, sulfamethoxazole, meropenem, methicillin, metronidazole, meropenem, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin, tetracycline, paromomycin, penicillin G, penicillin V, piperacillin, acanthromycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifapentine, rifaximin, roxithromycin Sulfadiazine, Silver Sulfadiazine, Spectinomycin, Streptomycin, Sulbactam, Sulfaacetyl, Sulfadiazine, Sulfamethoxazole, Sulfamethoxazole, Sulfamethoxazole, Sulfasalazine, Sulfaisoxazole, Tazobactam, Teicoplanin, Telavancin, Tetracycline, Temoxicillin, Tetracycline, Thiamphenicol, Ticarcillin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Acetylosin, Vancomycin, Enoxacin, Lomefloxacin, Naphazoline, Ciprofloxacin, Levofloxacin, Gatifloxacin, Moxifloxacin, Ofloxacin, Norfloxacin, Cefotetan, Cefnicillin, Cefadroxil, Cefalexin, Cephalosporin, Cephalothin, Cefmetazole, Cefotaxime, Latamoxef, Cephalosporin Pyroxime, cefuroxime aspirin, cefepime, dapavancin, demeclocycline, methacycline, ertapenem, fendamycin, gerdemycin, dextrin, posizolid, radizolid, torezolid, oritavancin, spiramycin, sulfadiazine, sulfonamidochrysoidine, gemifloxacin, naflufloxacin, trovafloxacin, grefloxacin, sparfloxacin, temafloxacin, teixobactin, melacidins, and combinations thereof.

[0122] In some embodiments, the present invention also provides candidate therapeutic agents or pharmaceutical compositions comprising said candidate therapeutic agents for the treatment or prevention of AMD, identified in any screening method herein.

[0123] compound

[0124] In some embodiments, this disclosure relates to a variety of compounds and / or compositions containing said compounds that can kill or inhibit the growth of AMD-associated microorganisms such as Bacillus megaterium.

[0125] The compounds described herein typically possess antibacterial activity, either alone or in combination with another agent. The compounds described herein can be bactericidal or bacteriostatic. A variety of compounds known to have antibacterial activity can be used in embodiments of the invention. For example, in some embodiments, the compounds described herein may include any alcohols, phenols, amines, sulfonamides, quinolones, anthraquinones, and / or benzoic acid-related compounds known to have antibacterial activity. Non-limiting examples of useful compounds include benzoic acid, benzyl alcohol, coumarins, catechols, polyphenols, chalcones (including glycyrrhizin chalcones), arbutins such as resveratrol and isoresveratrol, phenolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acids, caffeic acid, ferulic acid, chlorogenic acid, sinapic acid, flavonoids such as catechin, naringenin, quercetin, rutin, and succinate, tannins such as ellagic acid, and their esters and glycosides.

[0126] The compounds described herein are typically characterized by certain functional groups present in their molecular structure. For example, in some embodiments, the compounds described herein are characterized by having an alcohol hydroxyl group, a phenolic hydroxyl group, and / or a carboxylic acid group or a derivative thereof, such as esters, amides, carbonates, carbamates, sulfonates, glycosides, etc. In some embodiments, compounds having an amino group, a sulfonamide group, a thiol group, and / or a sulfoxide group or a sulfone group may also be used in the compositions and methods described herein.

[0127] The compounds described herein may have a polycyclic core structure, a bicyclic core structure, or a monocyclic core structure, each of which may be substituted by a variety of groups as described herein.

[0128] In some embodiments, the compounds described herein can be characterized by having Formula I or a pharmaceutically acceptable salt or ester thereof:

[0129]

[0130] To avoid any doubt, in Equation I, the ring structure Cy 1 With another ring structure Cy 2These two ring structures can be identical or different, connected by two linkers L and L', and these linkers are located in Cy. 1 With Cy 2 This forms another ring structure. It should be understood that Cy... 1 and Cy 2 Both are ring structures independent of L and L'.

[0131] In equation I, Cy 1 and Cy 2 Each is independently an optionally substituted cycloalkyl ring (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 3-7 Cycloalkyl rings), optionally substituted heterocycles such as optionally substituted 4-7 membered heterocycles (e.g., having one or two cyclic heteroatoms independently selected from N, O, and S), optionally substituted aryl rings (e.g., C... 6-10 Aryl rings (e.g., phenyl) or optionally substituted heteroaryl rings such as optionally substituted 5-10-membered heteroaryl rings (e.g., 5- or 6-membered heteroaryl rings having one or two cyclic heteroatoms independently selected from N, O, and S);

[0132] L and L' are each independently an empty or linking group (e.g., as described herein); as used herein, the term "linking group" is not limited to any particular type of linking group. For example, in some embodiments, the linking group may also form a ring structure with a portion to which it is attached, such as L and Cy. 1 Can be independent of Cy 2 Forming a ring structure;

[0133] L 2 It is an empty, optional substitution of C. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene or optionally substituted 4-7 membered heterocycloalkylene;

[0134] W is - OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d;-SR 5 ;-SO2R 5a ;-OCOR 2a -OSO2R 5a or

[0135] in:

[0136] R 1 and R 1a Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic.

[0137] R 3 and R 4 Each is independently hydrogen, -COR 2b -SO2R 5b Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic, or R 3 and R 4 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups;

[0138] R 2 R 2a R 2b R 5 R 5a and R 5b Each is independently hydrogen, -OH, -NR 3e R 4e Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic groups; and

[0139] R 3a R 3b R 3c R 3d R 3e R 4a R 4b R 4c R4d and R 4e Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optional C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or 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 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups.

[0140] Cy in Equation I 1 and Cy 2 It can be an aromatic or non-aromatic ring system, and in some cases may contain heteroatoms. In a preferred embodiment, Cy in Formula I... 1 and Cy 2 At least one of them is an aryl or heteroaryl ring, such as an optionally substituted C 6-10 Aryl ring, or optionally substituted 5-10 membered heteroaryl ring. For example, in some embodiments, Cy 1 and Cy 2 This ensures that the core structure of Formula I does not exhibit optional substituents. The structure can be any of the following:

[0141] Where L 2 -W can be attached to either the left or right ring, where L and L' can be either of those described herein, and suitable substituents for the ring are described herein.

[0142] In some implementations, Cy in Formula I 1 and Cy 2 All can be aryl or heteroaryl rings. For example, in some embodiments, compounds of formula I can have formula I-1:

[0143]

[0144] In some implementations, Ar in Formula I-1 1 and Ar 2 Each is an optional substitution of C.6-10 Aryl ring, or optionally substituted 5-10 membered heteroaryl ring. In some embodiments, Ar in Formula I-1 1 and Ar 2 Each is independently a optionally substituted phenyl ring or a 5- or 6-membered heteroaryl ring. For example, in some embodiments, Ar in Formula I-1 1 and Ar 2 Each of them independently is an optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring.

[0145] Formula I-1 typically has a multi-ring core structure. For example, in some implementations, Ar 1 and Ar 2 This ensures that the core structure of formula I-1 does not exhibit optional substituents. It can be any of the following:

[0146] Where L 2 -W can be attached to either the left or right ring, where L and L' are defined herein, and suitable substituents for the ring are described herein.

[0147] In some embodiments, the compound of formula I may have formula I-2:

[0148]

[0149] in:

[0150] m is 0, 1, 2, or 3.

[0151] R 10 Each time it appears, it is independently halogen, L. 2’ -W', optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 10 Or an R 10 Together with L or L' and the atoms to which they are bonded, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0152] Where -L 2’ -W' is selected independently each time it appears; and 1

[0153] L2’ Each time it appears, it is independently empty, and the C can be arbitrarily replaced. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene; and W' is independently -OR each time it appears. 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 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 For the definitions in this article, see, for example, Equation I.

[0154] It should be noted that the structural unit -L 2’ -W' and -L 2 Each instance of -W is selected independently and can be the same or different.

[0155] In some implementations, Cy in Equation I-2 1It is an optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring. In some embodiments, Cy in Formula I-2 1 C is an optional substitute 3-6 A cycloalkyl ring or optionally substituted 4-7 heterocycle, the heterocycle having one or two cyclic heteroatoms independently selected from N, O and S.

[0156] In some implementations, Cy 1 The core structure of Equation I-2 can be any of the following:

[0157] Where -L 2 -W is attached to the right-hand phenyl ring, L and L' are defined herein, and suitable substituents for the ring are described herein.

[0158] In a more preferred embodiment, Cy in Formula I 1 and Cy 2 All are phenyl rings. For example, in some embodiments, the compound of formula I-2 can have formula I-3:

[0159]

[0160] Where: L, L', L 2 W, R 10 And m are defined in this paper, see, for example, Equation I-2,

[0161] n is 0, 1, 2, or 3.

[0162] R 11 Each time it appears, it is independently halogen, -L 2’ -W', optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 11 Or an R 11 L or L' together with the atoms they are bonded to form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings; wherein L 2’ W' is defined in this paper, see, for example, the definition for equation I-2, and -L 2’ -W' is selected independently each time it appears.

[0163] In Equation I (e.g., any of Equations I-1 to I-3), L and L' can be either empty or linking bases independently. In some embodiments, L and L' in Equation I... ’ Each is independently empty, -C(O)-, or an optional substituted C. 1-4 Alkylene, optionally substituted C 2-4 -olefin, -O-, -S-, -NR 100 -、-S(O)-、-SO2-、-X 1 -G 1 -、-X 2 -G 2 -X 2a -or-CR 101 R 102 -,

[0164] in:

[0165] X 1 X 2 and X 2a C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 -olefin, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0166] G 1 and G 2 C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 alkenyl, -C(O)-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0167] Preferably, in some embodiments, -X 1 -G 1 -or-X 2 -G 2 -X 2a -Does not contain ON, SS, SN (except SO2-N) or -C(O)-S bonds;

[0168] R 100 and R 100a Each is an isolated pair (where applicable), hydrogen, COR 2c -SO2R 5c Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic; or R 100 or R 100a With R 10 or R 11 The groups form optionally substituted heterocyclic or heteroaryl rings;

[0169] R 101 R 101a R 102 and R 102a When present, they are independently hydrogen, -OH, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic group, or R 101 and R 102 、or R 101a and R 102a Together with the atoms they are bonded to, they form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; or R 101 and R 102 One of them, or R 101a and R 102a One of them and R 10 or R 11 The groups together form an optionally substituted cycloalkyl or heterocyclic ring; and

[0170] R 2c and R 5c Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group.

[0171] When the connecting base L or L ’ When forming a double bond with one of the cyclic carbons, it cannot be R. 101 and R 102 CR 101 R 102Because the oxidation state of carbon will exceed 4. In such cases, it should be understood that R 101 and R 102 One of them does not exist, and L or L' is CR as defined in this paper. 101 or CR 102 When L or L' forms a double bond with one of the ring carbons, it can be NR. 100 , where R 100 It is usually an isolated case. Similarly, other similar situations in this disclosure should be understood.

[0172] In some implementations, L and L' in Equation I are each independently empty, -O-, -C(O)-, -S-, -NR 100 -、-S(O)-、-SO2- or -CR 101 R 102 - In some embodiments, the compound of formula I has a formula according to any one of I-4 to I-5:

[0173]

[0174] in:

[0175] X 3 X 4 and X 5 Each of these can be independently: empty, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;as well as

[0176] R 10 R 11 R 100a R 101a R 102a W, L 2 , m and n are defined in this article.

[0177] In some embodiments, the compound has formula I-4, wherein X 3 and X 4 Each is independently -O-, -C(O)-, -S-, -NR 100a -or -SO2-. In some embodiments, the compound has formula I-5, wherein X 5 It is -O-, -C(O)-, -S-, -NR 100a -or -SO2-. In some implementations, R 100a It is hydrogen or an optional substituted C 1-4 alkyl.

[0178] L in Equation I (e.g., any sub-equation described herein, such as Equations I-1 to I-5) 2 Typically, the W group is empty, meaning it is directly attached to Cy. 2 In some implementations, L in Formula I 2 It could also be C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene groups. For example, the W group can be attached to Cy via a methylene or vinyl group. 2 .

[0179] Various W groups are suitable for compounds of formula I (e.g., any sub-formula described herein, such as formulas I-1 to I-5). In a preferred embodiment, the W group is independently –OH, -NH2, -SO2NH2, -SO2NH(C) each time it appears. 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted. In some embodiments, W in Formula I is –OH, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, Or -OC(O)-CH3.

[0180] As described in this article, L 2’ -W' can be selected for Cy in some implementations. 1 or Cy 2 Such as for Ar 1 Or Ar 2 Substituents. Where applicable, L in formula I (including any of the subforms described herein, such as formulas I-1 to I-5) 2’ Each occurrence can be independently empty, meaning the W' group is directly attached to Cy. 1 or Cy 2 For example, for Ar 1 Or Ar 2 As far as (where applicable), or C 1-4 Alkylene, C2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene groups. For example, the W' group can be attached to Cy via a methylene or vinyl group. 1 or Cy 2 For example, for Ar 1 Or Ar 2 In other words, when applicable, W' in formula I (including any sub-formulas described herein, such as formulas I-1 to I-5) may independently be –OH, -NH each time it appears. 2 -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, when applicable, each instance of W' in Formula I may be –OH, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, Or -OC(O)-CH3.

[0181] Various groups can be applied to R in any applicable formula I (e.g., any sub-formula described herein, such as formulas I-2 to I-5 when applicable). 10 and R 11 In some implementations, R 10 and R 11 Each of these can independently be F; Cl; –OH; -NH2; -SO2NH2; -SO2NH(C) each time it appears. 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group; -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); optionally independently selected from C 1-4 Alkyl, C1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 cycloalkyl; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl group. In some embodiments, R 10 and R 11 Each of these can independently be –OH; -NH2; -SO2NH2; -SO2NH(C) each time it appears. 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group; -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); C 1-4 Alkyl; or C 1-4 Alkyl group. In some embodiments, R 10 One or more instances and / or R 11 One or more instances of L can be independently selected as described herein. 2’ -W'.

[0182] Typically, m is 0, 1, or 2 when applicable; preferably, it is 1.

[0183] Typically, n is 0, 1, 2, or 3 when applicable; preferably, it is 1 or 2.

[0184] In some embodiments, the compounds described herein can be characterized by having Formula II or a pharmaceutically acceptable salt or ester thereof:

[0185] Cy10 ——L 10 ——Cy 11 -L 11 -w 10

[0186] Formula II,

[0187] in:

[0188] Cy 10 and Cy 11 Each is independently an optionally substituted cycloalkyl ring (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 3-7 Cycloalkyl rings), optionally substituted heterocycles (e.g., 4-7 membered heterocycles), optionally substituted aryl rings (e.g., C14-C24-C1 ... 6-10 aryl ring), optionally substituted heteroaryl ring (e.g., 5-10 membered heteroaryl ring), or optionally substituted ring structure comprising a cycloalkyl ring or heterocycle and an aryl or heteroaryl ring, wherein the ring structure may be a fused ring or otherwise connected.

[0189] L 10 It is an empty or connecting base;

[0190] L 11 It is an empty, optional substitution of C. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene,

[0191] W 10 Yes - OR 1 ;-COOR 1a ;-OCOOR 1a ;-COR 2 ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R 4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a -OSO2R 5a ;or

[0192] in:

[0193] R 1 and R 1a Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic.

[0194] R 3 and R 4 Each is independently hydrogen, -COR 2b -SO2R 5b Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic, or R 3 and R 4 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups;

[0195] R 2 R 2a R 2b R 5 R 5a and R 5b Each is independently hydrogen, -OH, -NR 3e R 4e Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic groups; and

[0196] R 3a R 3b R 3c R 3d R 3e R 4a R 4b R 4c R 4d and R 4e Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optional C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or 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 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups.

[0197] In some implementations, in Formula II, Cy 10 and Cy 11 At least one of them is an optional substitution of C. 6-10 An aryl ring or an optionally substituted 5-10 membered heteroaryl ring. In some embodiments, Cy 11 C is an optional substitute 6-10 Aryl rings or optionally substituted 5-10 membered heteroaryl rings. When Cy 11 When it is a bicyclic or polycyclic aryl or heteroaryl ring, L 10 -Cy 10 and L 11 -W 10 It can be independently connected to Cy via any ring. 11 In some implementations, Cy 11 It can have a fused ring structure comprising an aryl or heteroaryl ring and a cycloalkyl or heterocyclic structure. In such embodiments, Cy 11 It can be connected to L via an aryl or heteroaryl ring and any of a cycloalkyl or heterocyclic structure. 10 -Cy 10 and L 11 -W 10 Or alternatively, L 10 -Cy 10 and L 11 -W 10 One of them is linked to Cy via an aryl or heteroaryl ring. 11 , and L 10 -Cy 10 and L 11 -W 10 The other one is linked to Cy via a cycloalkyl or heterocyclic structure. 11 .

[0198] In some embodiments, the compound of formula II has at least one phenyl ring, which may have a Cy 10 -L10 -Cy 11 The following core structures:

[0199] Cy 10 It can be either the left or right ring in the above formula; that is, the chemical formula is not limited to a specific direction, where L 11 -W 10 It can be connected to either the left or right ring, and both rings can be optionally replaced.

[0200] In some embodiments, the compound of formula II may have Cy 10 -L 10 -Cy 11 The following core structures:

[0201] Cy 10 It can be either the left or right ring in the above formula; that is, the chemical formula is not limited to a specific direction, where L 11 -W 10 It can be connected to either the left or right ring, and both rings can be optionally replaced.

[0202] In some implementations, Cy in Formula II 10 and Cy 11 All are aryl or heteroaryl rings. In some embodiments, the compounds of formula II have formula II-1:

[0203] Ar 10 ——L 10 ——Ar 11 -L 11 -w 10

[0204] Formula II-1,

[0205] Among them, Ar 10 and Ar 11 Each is an optional substitution of C. 6-10 Aryl ring or optionally substituted 5-10 membered heteroaryl ring. In some embodiments, Ar in Formula II-1 10 and Ar 11 Each is independently a optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heteroaryl ring. In some embodiments, Ar in Formula II-1 10 and Ar 11 Each of these rings is independently a optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring. In some embodiments, Ar in Formula II-1 10 and Ar 11One is a bicyclic aryl or bicyclic heteroaryl ring, wherein each is optionally substituted, for example, in some embodiments, Ar 11 It can be an optionally substituted bicyclic aryl or bicyclic heteroaryl ring.

[0206] In some implementations, Cy in Formula II 11 It is a phenyl ring. In some embodiments, the compound of formula II has formula II-2:

[0207]

[0208] Among them, Ar 10 L 10 L 11 and W 10 In the definitions herein, see, for example, Equation II-1.

[0209] m is 0, 1, 2, or 3.

[0210] R 20 Each time it appears, it is independently halogen, -L 11’ -W 10’ Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 20 Or an R 20 and L 10 or L 11 Together with the atoms they are bonded to, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0211] Where -L 11’ -W 10’ Choose independently each time it appears;

[0212] Where L 11’ Each time it appears, it is independently empty, and the C can be arbitrarily replaced. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene; and W 10’ It is -OR independently each time it appears.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 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 In this paper, see, for example, Equation II. It should be noted that the structural unit -L 11’ -W 10’ and -L 11 -W 10 Each instance can be selected independently and can be the same or different.

[0213] In some implementations, Cy in Formula II 11 It is a benzo[a]-fused ring. In some embodiments, the compound of formula II has formula II-3:

[0214]

[0215] Among them, Ar 10 L 10 L 11 and W 10 In the definitions herein, see, for example, Equation II-1.

[0216] m is 0, 1, 2, or 3.

[0217] R 20 Each time it appears, it is independently halogen, -L 11’ -W 10’ Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 20 Or an R 20 and L 10 or L 11 Together with the atoms they are bonded to, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0218] Where L 11’ and W 10’ In this definition, see, for example, Equation II-2, and -L 11’ -W 10’ Choose independently each time it appears; and

[0219] Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocyclic ring, a phenyl ring, a 5- or 6-membered heteroaryl ring, wherein each of them may be optionally substituted.

[0220] In some implementations, Cy in Formula II 11 It is a benzo-fused bicyclic aryl or heteroaryl ring. For example, in some embodiments, Cy in Formula II 11 It can have the following core structure:

[0221]

[0222] Where L 10 -Cy 10 and L 11 -W 10 It can be independently connected to Cy through either of the two rings. 11 The phenyl ring may optionally be composed of 1-3 R atoms as defined herein. 20 Group substitution. For example, with regard to the benzothiophene ring, in some embodiments, L 10 -Cy 10 It can attach to a thiophene ring, while L 11 -W 10 It can attach to a phenyl ring, and vice versa, and in some cases, L 10 -Cy 10and L 11 -W 10 They can all attach to the same ring, such as the phenyl ring.

[0223] In some embodiments, the compound of formula II may have any of the following structures:

[0224]

[0225] Among them: Cy 10 L 10 R 20 m, R 21 n, R 100a L 11 and W 10 As defined herein, see, for example, Equations II and sub-equations, such as Equation II-3. In some embodiments, Cy 10 Ar is as defined for Equation II-3 10 .

[0226] In some embodiments, the compound of formula II-3 may have formula II-4:

[0227]

[0228] Among them: Ar 10 L 10 R 20 m, L 11 and W 10 In the definition herein, see, for example, Equation II-3.

[0229] n is 0 or 1,

[0230] R 21 Each time it appears, it is independently of halogen, oxo, or -L. 11’ -W 10’ Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; wherein L 11’ and W 10’ In this definition, see, for example, Equation II-2, and -L 11’ -W 10’ Choose independently each time it appears;

[0231] When the valence is allowed, X 10and X 11 Each of these can be independently: empty, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0232] Where R 100a It is an isolated pair (where applicable), hydrogen, COR 2c -SO2R 5c Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic; or R 100a With R 20 or R 21 The groups form optionally substituted heterocyclic or heteroaryl rings;

[0233] R 101a and R 102a When present, they are independently hydrogen, -OH, or halogen; C can be optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic group; or R 101a and R 102a Together with the atoms they are bonded to, they form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; or R 101a and R 102a One of them and R 20 or R 21 The groups together form an optionally substituted cycloalkyl or heterocyclic ring; and

[0234] R 2c and R 5c Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group;

[0235] Or R 20 or R 21 and L 10 X 10 or X 11 Together with the atoms they are bonded to, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings.

[0236] When X 10 or X 11 When forming a double bond with one of the cyclic carbons, it cannot be R. 101a and R 102a CR 101a R 102a Because the oxidation state of carbon will exceed 4. In such cases, it should be understood that R 101a and R 102a One of them does not exist, and X 10 or X 11 It is CR as defined in this article. 101a or CR 102a When X 10 or X 11 When forming a double bond with one of the cyclic carbons, it can be NR. 100a , where R 100a It is usually a solitary pair.

[0237] In some embodiments, the compound of formula II has formula II-5:

[0238]

[0239] Among them: Ar 10 L 10 R 20 m, R 21 , n, L 11 and W 10 For the definitions in this document, see, for example, Equation II-4.

[0240] Cy in Equation II (e.g., any of the sub-elements described herein, such as Equations II-1 to II-4) 10 and Cy 11 It can be linked directly or via multiple groups. For example, in some embodiments, L in formula II (e.g., formulas II-1 to II-5) 10 It is empty, -C(O)-, or C with optional substitution. 1-4 Alkylene, optionally substituted C 2-4 alkenyl, optionally substituted C 3-6Cycloalkylene, optionally substituted 4-7-membered heterocyclic cycloalkylene, optionally substituted phenylene, optionally substituted 5 or 6-membered heteroarylene, -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 -,

[0241] in:

[0242] X 1 X 2 and X 2a C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 alkenyl, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-7-membered heterocyclic cycloidene, optionally substituted phenylene, optionally substituted 5 or 6-membered heteroarylene, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0243] G 1 and G 2 C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 alkenyl, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-7-membered heterocyclic cycloalkylene, optionally substituted phenylene, optionally substituted 5 or 6-membered heteroarylene, -C(O)-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0244] Preferably, in some embodiments, -X 1 -G 1 -or-X 2 -G 2 -X 2a - Excludes ON, SS, SN (except SO2-N bonds) or -C(O)-S bonds;

[0245] X 12 X 13and X 13a C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 alkenyl, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-7-membered heterocyclic cycloidene, optionally substituted phenylene, optionally substituted 5 or 6-membered heteroarylene, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0246] and G 10 and G 11 Independently is -X 1 -G 1 -or-X 2 -G 2 -X 2a -;

[0247] In some implementations, preferably, -X 12 -G 10 -or–X 13 -G 11 -X 13a - It does not contain OO, ON, SS, SN (except SO2-N bonds), or -C(O)-S bonds or three (or more) consecutive heteroatoms, except for O-SO2-O, O-SO2-N and N-SO2-N;

[0248] R 100 and R 100a Each is an isolated pair (where applicable), hydrogen, COR 2c -SO2R 5c Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic groups;

[0249] R 101 R 101a R 102 and R 102a Each is independently hydrogen, -OH, or halogen; the C atoms can be optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 Alkoxy, optional substituted C3-6 Cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic group; or R 101 and R 102 、or R 101a and R 102a Together with the atoms they are bonded to, they form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0250] In some implementations, L in Formula II 10 It can be empty, and Cy 10 Directly with Cy 11 Connection. In some implementations, L in Formula II 10 It can be empty, -O-, -C(O)-, -S-, -NR 100 -、-S(O)-、-SO2- or -CR 101 R 102 - In some implementations, L in Formula II 10 It can be -X 1 -G 1 -or-X 2 -G 2 -X 2a -, where: X 1 X 2 and X 2a Independently, they are -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;and G 1 and G 2 Independently -C(O)-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -

[0251] In some implementations, L in Formula II 10 It can be –X 12 -G 10 - In some implementations, X 12 C is an optional substitute 2-4 Alkenyl, preferably And G 10 It is -X 1 -G 1 -or-X 2 -G 2 -X 2a -; where: X 1 X 2 and X 2aIndependently, they are -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;and G 1 and G 2 Independently -C(O)-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -

[0252] In some preferred embodiments, L in Formula II 10 It can be

[0253] In some embodiments, the compound of formula II may have the following core structure:

[0254] Where L 11 -W 10 It can be directly attached to any ring, preferably to one of two phenyl rings or to a single phenyl ring, wherein each ring can optionally be substituted by one or more suitable substituents described herein, for example, each substituent can be independently selected from F; Cl; –OH; -NH2; -SO2NH2; -SO2NH(C 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group; -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); optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 cycloalkyl; optionally independently selected from C 1-4alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkoxy; optionally substituted C 3-6 Cycloalkyl; optionally substituted 4-10 membered heterocyclic group; optionally substituted 5-10 membered heteroaryl group; or optionally substituted C 6-10 Aryl. For example, in some embodiments, L 11 -W 10 It is NH2 or NH(C) 1-4 An alkyl group is attached to one of two phenyl rings or to a single phenyl ring, while the other ring is optionally substituted by one or two substituents selected from methyl and methoxy groups.

[0255] In some specific embodiments, the compounds of formula II have the following formula according to formula II-6 or II-7:

[0256]

[0257] Where: L 11 W 10 R 20 And m are defined in this paper, see, for example, Equation II-3,

[0258] p is 0, 1, 2, 3, or 4.

[0259] R 22 Each time it appears, it is independently halogen, -L 11’ -W 10’ Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 22 Together with the atoms they are bonded to, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0260] Where L 11’ and W 10’ In this definition, see, for example, Equation II-2, and -L 11’ -W 10’ Choose independently each time it appears.

[0261] L in Equation II (e.g., any sub-equation, such as Equations II-1 to II-7) 11 It is usually empty, that is, W when applicable. 10 The group is directly attached to Cy 11 In some implementations, L in Formula II 11 It could also be C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene compounds. For example, W 10 The group can be attached to Cy via a methylene or vinyl group. 11 .

[0262] Multiple 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 functional groups are independently –OH, -NH2, -SO2NH2, -SO2NH(C) each time they appear. 1-4 Alkyl); -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, W in Formula II... 10 The functional groups are –OH, -OMe, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, Or -OC(O)-CH3.

[0263] As described in this article, L 11’ -W 10’ It can be selected for Cy in some implementation schemes 10 or Cy 11 Such as for Ar 10 Or Ar 11 Substituents. Where applicable, L in Formula II (including any of the subformulas described herein, such as Formulas II-1 to I-7) 11’ Each occurrence can be empty independently, that is, W 10’ The group is directly attached to Cy10 or Cy 11 For example, for Ar 10 Or Ar 11 As far as (where applicable), or C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene compounds. For example, W 10’ The group can be attached to Cy via a methylene or vinyl group. 10 or Cy 11 For example, for Ar 10 Or Ar 11 As applicable. When applicable, W in equation II (including any sub-equations described herein, such as equations II-1 to II-7) 10’ Each time it appears, it can be independently –OH or -NH. 2 -SO2NH2, -SO2NH(C 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, W in Formula II is substituted, when applicable. 10’ Each instance can be –OH, -OMe, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, or -OC(O)-CH3.

[0264] Various groups can be applied to R in any applicable formula II (e.g., formulas II-1 to II-7, when applicable). 20 R 21 and R 22 In some implementations, R 20 R 21 and R 22 Each of these can independently be F; Cl; –OH; -NH2; -SO2NH2; -SO2NH(C) each time it appears. 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group; -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); optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 cycloalkyl; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl group. In some embodiments, R 20 R 21 and R 22 Each of these can independently be F; Cl; –OH; -NH2, -SO2NH2, -SO2NH(C) each time it appears. 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group, -COOH; -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2; -OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); -O-(C 1-6 Alkyl); -O-(C 2-6 Alkenyl); optionally independently selected from C 1-4 Alkyl, C 1-6 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-6 Alkyl; or optionally independently selected from C 1-4Alkyl, C 1-6 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl. In some embodiments, R 20 R 21 and R 22 Each of these can independently be –OH, C, etc., each time it appears. 1-4 Alkyl, C 2-6 alkenyl or -O-(C 1-4 Alkyl group). In some embodiments, R 20 R 21 and R 22 Each of these can independently be –OH, -OMe, or – each time it appears. In some implementation schemes, R 20 One or more instances of R 21 One or more instances and / or R 22 One or more instances of L can be independently selected as described herein. 11’ -W 10’ .

[0265] Typically, m and p are 0, 1, 2 or 3 when applicable; preferably, they are 1 or 2.

[0266] Typically, n is 0, 1, or 2 when applicable; preferably, it is 0 or 1.

[0267] In some embodiments, the compound of formula II may have the formula according to any one of formulas II-8 to II-10:

[0268]

[0269] Where R 20 R 22 m and p are defined herein. In some implementations, m is 1 or 2, and p is 1, 2, or 3. In some implementations, R 20 and R 22 Each of these elements is independently F; Cl; –OH; -NH2, -SO2NH2, -SO2NH(C) each time it appears. 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group, -COOH; -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2; -OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); -O-(C 1-6 Alkyl); -O-(C2-6 Alkenyl); optionally independently selected from C 1-4 Alkyl, C 1-6 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-6 Alkyl; or optionally independently selected from C 1-4 Alkyl, C 1-6 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl group.

[0270] In some implementations, the structural unit in any applicable Formula II Can be selected

[0271]

[0272] In some specific embodiments, the compound of formula II can be:

[0273]

[0274]

[0275] Or its pharmaceutically acceptable salts or esters.

[0276] In some embodiments, the compounds described herein can be characterized by having Formula III or a pharmaceutically acceptable salt or ester thereof:

[0277] Ar 20 ——L 20 -W 20

[0278] Formula III,

[0279] Among them, Ar 20 It is an aryl ring with optional substitution (e.g., C). 6-10 Aryl ring) or optionally substituted heteroaryl ring (e.g., 5-10 membered heteroaryl ring);

[0280] L 20 It is an empty, optional substitution of C. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene,

[0281] W 20 Yes - OR 1 ;-COR 2 ;-COOR1a ;-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

[0282] in:

[0283] R 1 and R 1a Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic.

[0284] R 3 and R 4 Each is independently hydrogen, -COR 2b -SO2R 5b Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic, or R 3 and R 4 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups;

[0285] R 2 R 2a R 2b R 5 R 5a and R 5b Each is independently hydrogen, -OH, -NR 3e R 4e Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic groups; and

[0286] R 3a R 3b R 3c R 3d R 3e R 4a R 4b R 4c R 4d and R 4e Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optional C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or 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 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups.

[0287] In some implementations, Ar in Formula III 20 It is an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heteroaryl ring. For example, in some embodiments, Ar in Formula III 20 It can be an optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring. In some embodiments, Ar in Formula III 20 It can also be an optionally substituted bicyclic aryl or bicyclic heteroaryl ring, each of which is optionally substituted. In such embodiments, L 20 -W 20 It can be attached to any double ring.

[0288] In some implementations, Ar in Formula III 20 It can be an optionally substituted phenyl ring, wherein two adjacent substituents together with the carbon to which they are attached form an optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl ring.

[0289] For example, in some implementations, Ar in Formula III 20 It can be a benzofused bicyclic aryl or heteroaryl ring. For example, in some embodiments, Ar in Formula III... 20 It can have the following structure:

[0290]

[0291] Where –L 20 -W 20 It can be attached to either of the two rings, where either or both rings can be arbitrarily replaced.

[0292] In some embodiments, the compound of formula III may have formula III-1, III-2, or III-3:

[0293]

[0294] Where L 20 and W 20 In this article, as defined,

[0295] m is 0, 1, 2, or 3; n is 0, 1, 2, or 3;

[0296] R 30 and R 31 Each of these elements is independently a halogen, -L, each time it appears. 20’ -W 20’ Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; wherein –L 20’ -W 20’ Choose independently each time it appears; where L 20’ Each time it appears, it is independently empty, and the C can be arbitrarily replaced. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene; and W 20’ It is -OR independently each time it appears. 1 ;-COR 2 ;-COOR1a ;-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 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 In the definition presented herein, see, for example, Equation III.

[0297] Ring B is a 4-7 membered cycloalkyl ring, a 4-7 membered heterocyclic ring, a phenyl ring, a 5- or 6-membered heteroaryl ring, wherein each is optionally surrounded by 1-3 independently selected Rs. 31 replace;

[0298] When the valence is allowed, X 20 and X 21 Each of these can be independently: empty, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0299] Where R 100a It is an isolated pair (where applicable), hydrogen, COR 2c -SO2R 5c Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic; or R 100a and R 30 or R 31 One of them, together with the atoms they are bonded to, forms an optionally substituted heterocyclic or heteroaryl ring, such as an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 4- or 7-membered heterocyclic group;

[0300] R 101a and R 102a When present, they are independently hydrogen, -OH, or halogen; C can be optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic group, or R 101a and R 102a Together with the atoms they are bonded to, they form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; or R 101a and R 102a One of them and R 30 or R 31 The groups together form an optionally substituted cycloalkyl or heterocyclic ring; and

[0301] R 2c and R 5c Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group;

[0302] Or two adjacent R 30 Or two adjacent R 31 Or R 30 or R 31 and X 20 or X 21 Together with the atoms they are bonded to, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings.

[0303] When X 20or X 21 When forming a double bond with one of the cyclic carbons, it cannot be R. 101a and R 102a CR 101a R 102a Because the oxidation state of carbon will exceed 4. In such cases, it should be understood that R 101a and R 102a One of them does not exist, and X 20 or X 21 It is CR as defined in this article. 101a or CR 102a When X 20 or X 21 When forming a double bond with one of the cyclic carbons, it can be NR. 100a , where R 100a It is usually a solitary pair.

[0304] It should be noted that the structural unit – L 20’ -W 20’ and –L 20 -W 20 Each instance can be selected independently and can be the same or different.

[0305] In some embodiments, the compound of formula III may have any of the following structures:

[0306]

[0307] Where: R 30 m, R 31 n, R 100a L 20 and W 20 As defined herein, see, for example, Formula III and subformulas such as Formulas III-1 to III-3, where for tricyclic structures, the piperidine ring or morpholine ring may optionally be substituted.

[0308] L in Equation III (e.g., any sub-equation, such as Equations III-1 to III-3) 20 It is usually empty, that is, W 20 Groups directly attached to Ar 20 In some implementations, L in Formula III 20 It could also be C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene compounds. For example, W 20 The group can be attached to Ar via a methylene or vinyl group. 20 .

[0309] Multiple W 20The group applies to compounds of formula III (e.g., any sub-formula, such as formulas III-1 to III-3). In a preferred embodiment, W in formula III... 20 It can be –OH, -COOH, -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 alkyl acyl), -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, W in formula III (e.g., any subformula, such as formulas III-1 to III-3) is substituted. 20 The functional groups are –OH, -NH2, -SO2NH2, -SO2NH (acetyl). -C(O)-(O-C8 alkyl), -COOH or -OC(O)-CH3.

[0310] As described in this article, L 20’ -W 20’ It can be selected for use in some implementation schemes as Ar 20 Substituents. Where applicable, L in Formula III (including any of the subformulas described herein, such as Formulas III-1 to III-3) 20’ It can be empty independently each time it appears; that is, W when applicable. 20’ Groups directly attached to Ar 20 Or C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene compounds. For example, W, when applicable. 20’ The group can be attached to Ar via a methylene or vinyl group. 20 Where applicable, W in Equation III (including any of the sub-equations described herein, such as Equations III-1 to III-3) 20’ Each time it appears, it can be independently –OH, -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10alkenyl), -OC(O)NH2, -NH2, -SO2NH2, -SO2NH(C 1-4 Alkyl); -SO2NH(C 1-4 alkyl acyl), -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, W in Formula III is substituted, when applicable. 20’ Each instance can be –OH, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, -C(O)(O-C8 alkyl) or -OC(O)-CH3.

[0311] Various groups can be applied to R in any applicable Formula III (e.g., any sub-formula, such as Formulas III-1 to III-3). 30 and R 31 In some implementations, R 30 and R 31 Each of these can independently be F; Cl; –OH; -COOH; -OC(O)NH2; -OC(O)NH(C) each time it appears. 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 cycloalkyl; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl group. In some embodiments, R 30 and R 31 Each of these can independently be –OH, C, etc., each time it appears. 2-6 alkenyl, -O-(C 1-4 Alkyl group, -COOH, or -C(O)(OC) 1-10 Alkyl group). In some embodiments, R 30 and R 31 Each of these can be –OH or -OMe each time it appears. In some implementations, R 30 One or more instances and / or R 31 One or more instances of L can be independently selected as described herein. 20’ -W 20’ .

[0312] Typically, m is 0, 1, 2, or 3; preferably, it is 2 or 3. Typically, n is 1, 2, or 3.

[0313] In some embodiments, this disclosure also provides the following compounds: Or its pharmaceutically acceptable salts or esters.

[0314] In some embodiments, this disclosure also provides the following compounds: Or a pharmaceutically acceptable salt or ester thereof, wherein q is 1, 2, 3, 4, or 5, and Glu is a glucose residue. In some specific embodiments, this disclosure also provides

[0315] Its pharmaceutically acceptable salts or esters.

[0316] In some embodiments, the compounds described herein may also be alkaloids with antibacterial activity. As shown herein, certain indole alkaloids such as vinca alkaloids, glycyrrhizin, vendolidine, vincristine, etc., have shown effectiveness in killing microorganisms such as Bacillus megaterium. In some embodiments, the compounds described herein are characterized by formula IV-1 or IV-2, which are glycyrrhizin or vendolidine and derivatives:

[0317]

[0318] in:

[0319] R 40 It is hydrogen; -COR 2 ;-COOR 1a ;-SO2R 5a; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted ynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic;

[0320] R 41 Yes - OR 1 ;-OCOOR 1a ;-OCONR 3b R 4b ;-OCOR 2a ; or -OSO2R 5a n is 0 or 1;

[0321] R 42 R 43 and R 44 Each is independently hydrogen, -OR 1 OCOR 2a ; or -OSO2R 5a ;

[0322] L 30 Is it empty or methylene?

[0323] W 30 Yes - OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-OSO2NR 3d R 4d ;-OCOR 2a ; or -OSO2R 5a 1

[0324] in:

[0325] R 1 and R 1a Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic.

[0326] R 3 and R 4 Each is independently hydrogen, -COR 2b -SO2R 5b Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic, or R 3 and R 4 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups;

[0327] R 2 R 2a R 2b R 5 R 5a and R 5b Each is independently hydrogen, -OH, -NR 3e R 4e Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic groups; and

[0328] R 3a R 3b R 3c R 3d R 3e R 4a R 4b R 4c R 4d and R 4e Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optional C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or 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 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups.

[0329] In some embodiments, the compound of formula IV-1 or IV-2 has a formula according to one of formulas IV-3 to IV-6:

[0330]

[0331] Where R 45 It is either hydrogen or methyl.

[0332] In some implementations, R of any one of formulas IV-1 to IV-6 40 It can be hydrogen, C 1-4 Alkyl or C 1-4 Alkyl group.

[0333] L in formulas IV-1 to IV-6 30 It is usually empty. However, in some implementations, L in formulas IV-1 to IV-6 30 It can also be CH2.

[0334] W in formulas IV-1 to IV-6 30 Typically, these are carboxylic acid derivatives, amine derivatives, or alcohol derivatives that can be used in the compositions and methods described herein. The naturally occurring indole alkaloid glycyrrhizin contains a CO2Me group as a W... 30 , and L 30 The CO2Me group is empty. It can be converted to the corresponding acid, amide, etc., via conventional conversion, or reduced or converted to an amine via rearrangement such as the Curtius rearrangement. In some embodiments, W in formulas IV-1 to IV-6... 30 It can be –OH, -NH2, -OSO2NH2, -COOH, -C(O)(OC) 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 The alkoxy group, -OH, -NH2, and fluorine are substituted with 1-3 substituents. In some embodiments, W in formulas IV-1 to IV-6... 30 It can be –OH, -NH2, -OSO2NH2, -C(O)-(O-C8 alkyl), -COOH or -OC(O)NH2.

[0335] In some specific embodiments, the compound may have the following structure:

[0336]

[0337] In some embodiments, the compounds described herein may also be glycosides with antibacterial activity, or pharmaceutically acceptable salts or esters thereof. As shown herein, certain glycosides, such as ginsenosides and gallic acid glycosides, have shown effective killing of microorganisms such as Bacillus megaterium. Other useful glycosides include any of those glycosides known in the art to have antibacterial activity, which may, for example, include glycosides characterized by their respective aglycones being phenolic compounds, flavonoids, coumarins, benzoic acid, or sterols. Typically, glycosides are glucosides, but other glycosides may also be used. In some embodiments, the glycosides may be characterized as amphiphilic, which can disrupt biofilms and confer antimicrobial activity. In some embodiments, the glycosides may also be characterized as saponins, which, for example, include a variety of plant-derived glycosides that can act as “surfactants” and can contribute to the killing of bacteria.

[0338] In some implementations, the glycosides described herein can be characterized by formula V:

[0339]

[0340] Each R 50 Independently, it is hydrogen, -L 50 -D, oxygen protecting group or sugar residue;

[0341] L 50 It is empty or –C(O)-;

[0342] D is an aryl group that is optionally substituted (e.g., C). 6-10 Aryl), optionally substituted heteroaryl (e.g., 5- to 14-membered heteroaryl), optionally substituted fused rings comprising two or more independently selected aryl, heteroaryl, cycloalkyl, and heterocyclic groups (e.g., 8- to 14-membered, e.g., benzofused cycloalkyl / heterocyclic, pyridinic fused cycloalkyl / heterocyclic), or steroid residues having the formula VA:

[0343]

[0344] When the valence is allowed It can be via the steroid skeleton or any R 51 Groups are attached to formula VA.

[0345] Where R 51 Each time it appears independently of an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted -OH group with an oxoprotective group, oxo group, halogen group, optionally substituted cycloalkyl group, optionally substituted alkoxy group, optionally substituted cycloalkoxy group, optionally substituted amino group, optionally substituted phenyl group, optionally substituted heteroaryl group, or optionally substituted heterocyclic group, or two R groups. 51The groups, together with the atoms they are bonded to, form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0346] m is an integer from 1 to 8; and

[0347] Where -L 50 -D is selected independently each time it appears.

[0348] In some implementations, each R 50 It is hydrogen.

[0349] In some implementation schemes, one to four R 50 -L can be selected independently. 50 -D. When there are two or more -L... 50 When the -D units are attached to the pyranose units in formula V, they are preferably identical. In some embodiments, one or more (e.g., 1 or 2) R 50 It can be 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.

[0350] L in formula V 50 It can be an empty or carbonyl group, i.e., -C(O)-, depending on whether the linking group is a phenol –OH or COOH group from benzoic acid or a heteroaryl counterpart.

[0351] Various residues can be used as D, which are typically residues from phenolic compounds, coumarins, flavonoids, or sterols, and in some embodiments can have antibacterial activity without a glycoside unit.

[0352] In some implementations, D can be a ring selected from the following optional substitutions:

[0353]

[0354] in

[0355] R 100a It is a lone pair (where applicable), hydrogen, nitrogen protecting group, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic; or R 100a It can form optionally substituted heterocyclic or heteroaryl rings with phenyl or pyridyl rings;

[0356] in It can be connected to D from any available location, and

[0357] Each ring system of D is optionally substituted by 1-5 (e.g., 1, 2, or 3) substituents, each substituent being independently selected from -OH; -COOH; -C(O)(OC) 1-10 Alkyl); -C(O)(OC 2-10 alkenyl); -OC(O)NH2; -OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); -NH2; -SO2NH2; -SO2NH(C 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group; halogen; optional substituted C 1-6 Alkyl; optionally substituted C 2-6 alkenyl; optionally substituted C 2-6 alkynyl group; optionally substituted C 3-6 cycloalkyl; optionally substituted C 1-6 Alkoxy; optionally substituted C 3-6 Cycloalkoxy; optionally substituted amino group; optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group.

[0358] In some embodiments, each ring system of D as shown above may optionally be substituted with 1-5 substituents, each substituent being independently selected from F; Cl; –OH; -COOH; -C(O)(OC 1-10 Alkyl); -C(O)(OC 2-10 alkenyl); -OC(O)NH2; -OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); -NH2; -SO2NH2; -SO2NH(C 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group); optionally independently selected from C 1-4 alkyl groups substituted with 1-3 substituents at C 1-4 Alkyl; C 1-4 Alkyl groups, -OH, -NH2, and fluorine; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6cycloalkyl; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl group.

[0359] In some implementation schemes, D can be selected from:

[0360]

[0361] Each phenol OH group is optionally linked to a sugar (such as glucose) via a glycosidic bond.

[0362] In some embodiments, D is derived from sterols. For example, in some embodiments, D is...

[0363]

[0364] Where R 52 It is an alkyl group that is optionally substituted or an alkenyl group that is optionally substituted.

[0365] Each of the remaining -OH groups in D is optionally linked to a sugar via a glycosidic bond.

[0366] Preferably, R 52 It can be

[0367] In any of the embodiments described above, the glycoside may have formula V-1 or V-2:

[0368]

[0369] In some embodiments, the glycoside may be a compound selected from the following:

[0370]

[0371] In some embodiments, the compounds herein may be selected from any one or more of the following: benzoic acid, benzyl alcohol, coumarins, catechols, polyphenols, chalcones (including glycyrrhizin chalcones), arbutins such as resveratrol and isoresveratrol, phenolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acids, caffeic acid, ferulic acid, chlorogenic acid, sinapic acid, flavonoids such as catechin, naringenin, quercetin, rutin, succinate, tannins such as ellagic acid, and their pharmaceutically acceptable salts or esters and glycosides.

[0372] In some embodiments, the compounds described herein may be any one or more of compounds 1-8 or their pharmaceutically acceptable salts or esters.

[0373]

[0374] The compounds described herein can generally be isolated from natural sources or, alternatively, prepared via conventional chemical synthesis. For example, each of compounds 1-8 is commercially available and has been identified as a component of a plant. Unless otherwise indicated, in any embodiment described herein, the compounds may be derived from synthetic sources. Unless otherwise indicated, in any embodiment described herein, the compounds may be present in an isolated form or in a substantially pure form. It should be understood that the term "isolated form" refers to a compound that has been isolated and / or enriched from its source, such as a synthetic reaction mixture or a natural source. Typically, such isolated compounds are also substantially pure, for example, with a purity greater than 80%, 85%, 90%, 95%, or higher by weight. It should also be understood that compositions containing compounds in an isolated or substantially pure form, such as pharmaceutical compositions, mean that the compounds have been isolated or purified, i.e., in an isolated or substantially pure form, prior to mixing with other components of the composition.

[0375] Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize applicable compounds are known in the art and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Watts, 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, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0376] Pharmaceutical Composition

[0377] Some embodiments involve pharmaceutical compositions comprising one or more compounds of this disclosure and optionally pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises compounds of this disclosure and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Suitable excipients, without limitation, include, for example, encapsulating materials or additives such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's *The Science and Practice of Pharmacy*, 21st edition, ARGennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses a variety of excipients for formulating pharmaceutical compositions and known techniques for their preparation.

[0378] Pharmaceutical compositions may comprise any one or more compounds disclosed herein. For example, in some embodiments, a pharmaceutical composition comprises a compound of formula I, II, III, IV-1, IV-2, V, any of its subforms, or any one or more of compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any embodiment described herein, a pharmaceutical composition may comprise a compound selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any embodiment described herein, a pharmaceutical composition may also be free of or substantially free of compounds selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof.

[0379] Pharmaceutical compositions may comprise various amounts of the compounds disclosed herein, depending on a variety of factors, such as the intended use and potency of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein and pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of the compounds disclosed herein may be an amount effective in treating AMD as described herein (e.g., wet AMD, dry AMD), which may depend on the recipient of treatment, the stage and severity of AMD, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered. In some embodiments, a therapeutically effective amount of the compounds disclosed herein may be an amount effective in killing, for example, microorganisms in the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, such as intestinal microorganisms like Bacillus megaterium, or inhibiting their growth. In some embodiments, a therapeutically effective amount of the compounds disclosed herein may be an amount that effectively kills, for example, microorganisms in the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the gut, or inhibits their growth. These microorganisms are, for example, one or more selected from: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophalophora haematobacterium, Bacillus licheniformis, or Xanthomonas aeruginosa. In some embodiments, a therapeutically effective amount of the compounds disclosed herein may be an amount that effectively treats symptoms of drusen, such as reducing drusen-like lesions.

[0380] In various embodiments, the pharmaceutical compositions described herein can be used to treat AMD and / or kill or inhibit the growth of microorganisms described herein, such as *Bacillus megaterium*. The microorganisms described herein are not particularly limited and generally refer to microorganisms such as bacteria found in the intraocular space of a subject's eye, more preferably, AMD-associated microorganisms, such as those enriched in AMD patients. Unless otherwise specified, in any embodiment described herein, the microorganism may include *Bacillus megaterium*. In some embodiments, the microorganism may include one or more selected from: *Staphylococcus epidermidis*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Staphylococcus hemolyticus*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Bacillus cereus*, *Bacillus megaterium*, *Lactobacillus reuteri*, *Gardnerella vaginalis*, *Enterococcus faecalis*, *Fibrophagia harzianum*, *Bacillus licheniformis*, or *Xanthomonas orientalis*.

[0381] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other ingredients in the pharmaceutical compositions described herein will vary depending on the identity, body size, and / or condition of the subject being treated and further on the route of administration of the composition.

[0382] The pharmaceutical compositions described herein can be formulated for delivery via any known route of delivery, including but not limited to oral, injectable or infusionable, topical, intraocular, and inhalation routes.

[0383] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulation can exist in discrete units, such as capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients used to prepare compositions for oral administration are known in the art. Suitable excipients, without limitation, include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, astragalus gum, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0384] In some embodiments, the pharmaceutical composition is formulated for injection or infusion, such as intravenous injection or infusion, subcutaneous or intramuscular injection, or intraocular injection, such as intravitreal injection. The injectable / infusionable formulation may be, for example, an aqueous solution, suspension, reservoir, implant, or emulsion. Excipients used to prepare the injectable / infusionable formulation are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, wheat germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof. In some embodiments, the pharmaceutical composition is formulated for intraocular administration, such as intravitreal injection.

[0385] In some embodiments, the pharmaceutical composition is formulated for topical application. Topical formulations and excipients used in topical formulations are well known in the art.

[0386] The compounds disclosed herein can be used as monotherapy, in combination with each other, or in combination therapy. For example, in some embodiments, the pharmaceutical compositions described herein may further comprise another antibiotic and / or an anti-VEGF agent. In some embodiments, such antibiotics and / or anti-VEGF agents may be contained in separate dosage forms. In some embodiments, any commercially available (e.g., FDA-approved) antibiotic and anti-VEGF agent may be used in combination with the compounds and compositions herein. In some embodiments, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or a azole antibiotic, or a combination thereof. For example, in some implementations, the antibiotic may include one or more of the following: β-lactam antibiotics, including penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacancillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pimecrolimus, pimecrolimus, ticarcillin; cephalosporins such as cefetrazol, cefadroxil, cefalexin, cephalosporin glycine, ceflonine, cefotaxime, cephalothin, etc. Cefoperazone, ceftriaxone, cefotaxime, cefoxitin, cefazolin, cefradine, cefotaxime, cefotiazole, cefaclor, cefamandole, cefmetazole, cefnicotinic acid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefazolin, cefcarpine, cefodamide, cefdinir, ceftolun, cefotaxime, cefixime, cefotaxime, cefotiazine, cefotaxime, cefoperazone, cefpodoxime, cefoperazone, cefbufen, ceftiofur, cefotaxime, cefazolin, cefazolin, ceftriaxone, cefoperazone Ketones, Ceftazidime, Cefixime, Cefepime, Cefrenaline, Cefotaxime, Cefazolin, Cefpirome, Cefquinoxime, Cefpyrap, Cefalorin, Cefchlorazine, Cefolomide, Cefperazine, Cefcarne, Cefdrolone, Cefpyrone, Ceftriazole, Cefvetril, Cefmatilen, Cefmepidium, Cefvexin, Cefoxazole, Cefrotitol, Cefsulpimethazone, Cefuroxime, Cefuroxime, Cefthiazoline, Thiamethoxazole, Mono-lactamazole, β-carboxamide - Lactamase inhibitors, methicillins; aminoglycoside antibiotics, including streptomycin, gentamicin, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribostamycin, simvamycin, azithromycin, dibekacin, sisomicin, netilmicin, paromomycin, brevicone, etc.; tetracycline antibiotics, including tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; chloramphenicol antibiotics, including chloramphenicol, thiamphenicol, etc.Macrolide antibiotics, including erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, midecamycin, josamycin, azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, etc.; glycopeptide antibiotics, including vancomycin, norvancomycin, teicoplanin, etc.; quinolone antibiotics, including norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, bexifloxacin; nitroimidazole antibiotics, including metronidazole... Antagonists include tinidazole, ornidazole, etc.; rifamycin antibiotics, including rifampin; echinocandins; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymyxin B combinations such as polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / bacitracin, etc.

[0387] In some implementation schemes, the antibiotic may be selected from amikacin, amoxicillin, ampicillin, arsenamine, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalosporin, cefalothin, cefamandole, cefazolin, cefdinir, ceftoranol, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, cefbufenozide, cefuroxime, chloramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dapoxetine, dapsone, dapoxetine, dicloxacillin, erythromycin, and doripenem. Doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, clocabimethionine, sulfamethoxazole, meropenem, methicillin, metronidazole, meropenem, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin, tetracycline, paromomycin, penicillin G, penicillin V, piperacillin, acanthromycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifapentine, rifaximin, roxithromycin Sulfadiazine, Silver Sulfadiazine, Spectinomycin, Streptomycin, Sulbactam, Sulfaacetyl, Sulfadiazine, Sulfamethoxazole, Sulfamethoxazole, Sulfamethoxazole, Sulfasalazine, Sulfaisoxazole, Tazobactam, Teicoplanin, Telavancin, Tetracycline, Temoxicillin, Tetracycline, Thiamphenicol, Ticarcillin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Acetylosin, Vancomycin, Enoxacin, Lomefloxacin, Naphazoline, Ciprofloxacin, Levofloxacin, Gatifloxacin, Moxifloxacin, Ofloxacin, Norfloxacin, Cefotetan, Cefnicillin, Cefadroxil, Cefalexin, Cephalosporin, Cephalothin, Cefmetazole, Cefotaxime, Latamoxef, Cephalosporin Pyrazoxime, cefuroxime axetine, cefepime, dapavancin, demecycline, methacycline, ertapenem, fendamycin, geldmycin, chlorhexidine, posizolid, radizolid, torezolid, oritavancin, spiramycin, sulfadiazine, sulfonamide, gemifloxacin, naflufloxacin, trovafloxacin, grefloxacin, sparfloxacin, temafloxacin, teixobactin, melacidins, and combinations thereof. Antibiotics may be in any form, such as in the form of their respective pharmaceutically acceptable salts or mixtures thereof.Antibiotics can be formulated and administered according to their known routes of administration, and there are no particular restrictions.

[0388] Anti-VEGF drugs typically include biologics that target VEGF, such as ranibizumab, aflibercept, bevacizumab, and conbercept.

[0389] Treatment

[0390] The compounds disclosed herein can be used as therapeutically active substances for the treatment and / or prevention of diseases or conditions associated with infections of microorganisms described herein, such as *Bacillus megaterium* (e.g., ocular infections, such as those in the intraocular space). As shown in the Examples section, representative compounds of this disclosure have demonstrated potent bactericidal or inhibitory effects against the representative microorganism *Bacillus megaterium* in in vitro tests. Furthermore, examples show that antibiotics such as vancomycin can reduce drusen-like lesions caused by *Bacillus megaterium* by killing or inhibiting *Bacillus megaterium* in vivo, for example, in the macaque model described herein.

[0391] Therefore, in various embodiments, this disclosure also provides methods for treating infections of microorganisms such as Bacillus megaterium and for treating or preventing diseases or conditions (such as AMD) associated with such infections using compounds of this disclosure or pharmaceutical compositions herein.

[0392] Unless otherwise specified, in any of the embodiments described herein, the infection may include an ocular infection, such as one within the intraocular space. Unless otherwise specified, in any of the embodiments described herein, the microorganism may include *Bacillus megaterium*. In some embodiments, the microorganism may include one or more selected from: *Staphylococcus epidermidis*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Staphylococcus haemolyticus*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Bacillus cereus*, *Bacillus megaterium*, *Lactobacillus reuteri*, *Gardnerella vaginalis*, *Enterococcus faecalis*, *Fibrophagia harzianum*, *Bacillus licheniformis*, or *Xanthomonas orientalis*.

[0393] In various embodiments, the compounds of this disclosure can be used to kill or inhibit the growth of microorganisms described herein, such as Bacillus megaterium. In some embodiments, the compounds of this disclosure can be used to treat or prevent AMD, such as dry or wet age-related macular degeneration with drusen-like symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerating drusen), for example, dry or wet age-related macular degeneration with soft drusen-like symptoms. The compounds of this disclosure can be used alone, in combination with each other, or in combination with another antibiotic and / or anti-VEGF drug, for example, as described herein.

[0394] In some embodiments, this disclosure provides methods for killing microorganisms described herein, such as Bacillus megaterium, or inhibiting their growth. In some embodiments, the method includes contacting the microorganism with an effective amount of a compound of this disclosure or a pharmaceutical composition described herein. In some embodiments, the contact may be in vitro, ex vivo, or in vivo.

[0395] In some embodiments, this disclosure also provides methods for killing or inhibiting the growth of microorganisms described herein, such as Bacillus megaterium, in subjects in need. In some embodiments, the method includes administering to a subject a compound of this disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V, any of their subforms, or any one or more of compounds 1-8, or a pharmaceutically acceptable salt or ester thereof). Unless otherwise indicated, in any embodiment described herein, the method may include administering to a subject a compound selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any embodiment described herein, the method may also include administering to a subject a pharmaceutical composition that is free from or substantially free from compounds selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the compound or pharmaceutical composition is administered in an amount effective in killing or inhibiting the growth of microorganisms in the subject, such as those in the eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestines. In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject's eye is infected with a microorganism described herein, such as Bacillus megaterium. In some embodiments, the method further includes identifying, or having identified, the subject as being infected with, for example, a microorganism such as Bacillus megaterium in the intraocular space. In some embodiments, antibiotics and / or anti-VEGF drugs, such as those described herein, are further administered to the subject. In such embodiments, antibiotics and / or anti-VEGF drugs may be administered to the subject simultaneously with or sequentially in any order with the compounds disclosed herein or the pharmaceutical compositions herein.

[0396] In some embodiments, this disclosure provides methods for treating or preventing AMD in a subject in need. In some embodiments, the method includes administering to a subject a therapeutically effective amount of a compound of this disclosure (e.g., compounds of formulas I, II, III, IV-1, IV-2, V), a compound of any of its subforms, or any one or more of compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any embodiment described herein, the method may include administering to a subject a compound selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. Unless otherwise indicated, in any embodiment described herein, the method may also include administering to a subject a pharmaceutical composition that is free from or substantially free from compounds selected from compounds 1-8, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the method further includes administering to a subject an antibiotic and / or an anti-VEGF drug, for example, as described herein. In some embodiments, AMD can be dry or wet age-related macular degeneration with drusen-like symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), such as dry or wet age-related macular degeneration with soft drusen-like symptoms. In some embodiments, the method further includes identifying or having identified the subject as being infected, for example, with microorganisms such as *Bacillus megaterium* in the intraocular space. In some embodiments, the subject is infected, for example, with microorganisms such as *Bacillus megaterium* in the intraocular space. In some embodiments, the method includes administering a compound or pharmaceutical composition to the subject in an amount that effectively kills or inhibits the growth of microorganisms such as *Bacillus megaterium* in the subject, for example, in the subject's eye (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestine.

[0397] The application described herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, topical, intraocular, intravitreal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, administration may be oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, administration is intravitreal.

[0398] Dosing regimens, such as dosage and frequency, will vary depending on a variety of factors, including the recipient of treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0399] extract

[0400] In one aspect, this disclosure also provides extracts of certain traditional Chinese medicines (TCMs) possessing antibacterial activity. The term "traditional Chinese medicine" should be interpreted broadly to include both herbal and non-herbal TCMs, such as those described in the relevant sections of the Pharmacopoeia of the People's Republic of China (current edition). As detailed in the Examples section, several TCMs have been found to be active against *Bacillus megaterium*, a representative microorganism of this article. While some isolated components from these TCMs have been further identified as active against *Bacillus megaterium*, the extracts themselves can be used to treat infections and related diseases or conditions of the microorganisms described herein, such as AMD.

[0401] Therefore, in some embodiments, this disclosure provides a method for treating or preventing AMD in a subject in need, the method comprising administering to the subject an extract from one or more TCMs selected from: licorice (e.g., Glycyrrhiza uralensis), white peony root (e.g., Cynanchum otophyllum), forsythia (e.g., Forsythia suspense), immature bitter orange (e.g., Citrus aurantium L.), rehmannia root (e.g., Rehmannia glutinosa Libosch), tangerine peel (e.g., Citrus reticulata Blanco), and notoginseng (e.g., Panax notoginseng). In some embodiments, AMD may be dry or wet age-related macular degeneration with drusenic symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), such as dry or wet age-related macular degeneration with soft drusenic symptoms. In some embodiments, the method further includes identifying or having identified the subject as being infected, for example, with microorganisms such as Bacillus megaterium, in the intraocular space described herein. In some implementations, the subject is infected, for example, with microorganisms such as Bacillus megaterium in the intraocular space.

[0402] In some embodiments, this disclosure provides methods for killing or inhibiting the growth of microorganisms described herein, or methods for treating infections caused by microorganisms such as Bacillus megaterium, in subjects in need, comprising administering to the subject an extract from one or more TCMs selected from: licorice (e.g., Glycyrrhiza uralensis), white peony root (e.g., Cynanchum otophyllum), forsythia (e.g., Forsythia suspense), immature bitter orange (e.g., Citrus aurantium L.), rehmannia root (e.g., Rehmannia glutinosa Libosch), tangerine peel (e.g., Citrus reticulata Blanco), and notoginseng (e.g., Panax notoginseng). In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject's eye is infected with microorganisms such as Bacillus megaterium. In some embodiments, the method further includes identifying or having identified the subject as having an infection of microorganisms such as Bacillus megaterium, for example, in the intraocular space. In some implementations, subjects are further administered antibiotics and / or anti-VEGF drugs, for example, as described herein.

[0403] In some embodiments, the extract may be an extract of a single TCM. For example, in some embodiments, the method includes administering an extract of licorice (e.g., Glycyrrhiza uralensis) to the subject. In some embodiments, the method includes administering an extract of white peony root (e.g., Cynanchum otophyllum) to the subject. In some embodiments, the method includes administering an extract of forsythia (e.g., Forsythia suspense) to the subject. In some embodiments, the method includes administering an extract of immature bitter orange (e.g., Citrus aurantium L.) to the subject. In some embodiments, the method includes administering extracts of rehmannia root (e.g., Rehmannia glutinosa Libosch) and tangerine peel (e.g., Citrus reticulata Blanco) to the subject. In some embodiments, the method includes administering an extract of notoginseng (e.g., Panax notoginseng) to the subject.

[0404] In some embodiments, the extract may be an extract of a combination of two or more TCMs. For example, in some embodiments, the method includes administering to a subject an extract from two or more TCMs selected from: licorice (e.g., Glycyrrhiza uralensis), white peony root (e.g., Cynanchum otophyllum), forsythia (e.g., Forsythia suspense), immature bitter orange (e.g., Citrus aurantium L.), rehmannia root (e.g., Rehmannia glutinosa Libosch), tangerine peel (e.g., Citrus reticulata Blanco), and notoginseng (e.g., Panax notoginseng). In some embodiments, the method includes administering to a subject an extract derived from: (a) one of the following TCMs: licorice (e.g., Glycyrrhiza uralensis), white peony root (e.g., Cynanchumotophyllum), forsythia (e.g., Forsythia suspense), immature bitter orange (e.g., Citrus aurantium L.), rehmannia root (e.g., Rehmannia glutinosa Libosch), tangerine peel (e.g., Citrus reticulata Blanco), and notoginseng (e.g., Panax notoginseng); and (b) one or more other TCMs. In some embodiments, the method includes administering to a subject an extract derived from: (a) 1-7, but not all, TCMs in any combination, each independently selected from licorice, white peony root, forsythia, immature bitter orange, rehmannia root, tangerine peel, and notoginseng; and optionally (b) one or more other TCMs.

[0405] The extracts described herein are typically prepared according to standard practices for TCMs. See, for example, the Examples section. When using two or more TCMs, extracts can be prepared by: extracting each TCM individually (or any subgroup of the TCMs extracted) and then combining these extracts; or by extracting two or more TCMs together. Typically, the extracts are aqueous extracts. In some embodiments, non-aqueous extracts may also be useful. It should also be noted that for some TCMs, multiple plant parts may be useful, such as leaves, stems, roots, fruits, seeds, etc. In the embodiments described herein, the extracts are not limited to any particular part of the TCM plant, where applicable.

[0406] The extract described herein may be present or administered in liquid, semi-solid, or solid form, or any other form. For example, the extract may be administered as an aqueous solution, suspension, or emulsion. Alternatively, the extract may be formulated into capsules, tablets, powders, etc., and administered accordingly, usually orally. Administration of the extract may follow typical practices regarding TCM and is not limited to a specific route of administration. Dosing regimens such as dosage and frequency may be adjusted based on a variety of factors, such as the recipient of treatment, the disease or condition being treated and its severity, the composition containing the extract, the time of administration, the route of administration, the duration of treatment, the potency of the extract, its clearance rate, and whether another drug is administered concurrently. In some embodiments, the extract is administered in an amount that effectively kills or inhibits the growth of microorganisms described herein, such as Bacillus megaterium, in the subject, for example, in the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestines.

[0407] antibiotic

[0408] As discussed herein, the present invention is based in part on the unexpected discovery that the intraocular environment is not sterile and that certain intraocular microbiota may be a cause of AMD. Therefore, any antibiotic, such as those known in the art, can be used to treat infections caused by the microorganisms described herein and can be used to treat or prevent AMD. Accordingly, in some embodiments, this disclosure also provides methods for killing or inhibiting the growth of microorganisms such as *Bacillus megaterium* in a subject in need, methods for treating infections caused by the microorganisms described herein (e.g., ocular infections, such as those in the intraocular space), and / or methods for treating or preventing diseases or conditions associated with the microorganisms or infections, such as AMD, comprising administering an effective amount of antibiotic to the subject. In some embodiments, any commercially available antibiotic may be used, for example, those approved by the U.S. FDA. In some embodiments, the antibiotic may be characterized as a broad-spectrum antibiotic. In some embodiments, the antibiotic may be an antibiotic against Gram-positive bacteria. In some embodiments, the subject has AMD. In some embodiments, the subject does not have AMD. In some embodiments, the subject is at risk of developing AMD. In some embodiments, the subject has an ocular infection, such as infection by one of the microorganisms described herein, such as *Bacillus megaterium*. In some embodiments, AMD can be dry or wet age-related macular degeneration with drusen-like symptoms (including hard drusen, soft drusen, mixed drusen, and / or degenerated drusen), such as dry or wet age-related macular degeneration with soft drusen-like symptoms. In some embodiments, the method further includes identifying or having identified the subject as being infected, for example, with microorganisms described herein, such as *Bacillus megaterium*, in the intraocular space. In some embodiments, the subject is infected, for example, with microorganisms described herein, such as *Bacillus megaterium*, in the intraocular space. In some embodiments, the subject is further administered an anti-VEGF drug, for example, as described herein.

[0409] The compounds disclosed herein (see, for example, the Compounds section) generally have antibacterial activity and are therefore antibiotics. However, the antibiotics described in this section may be independent of the compounds disclosed herein (e.g., as defined herein). In some embodiments, the antibiotic is also a compound of this disclosure. In some embodiments, the antibiotic is not a compound of this disclosure. In some embodiments, the antibiotic and the compounds of this disclosure are used together in combination therapy, and they may be administered simultaneously (e.g., in a single dosage form) or sequentially to the subject in need.

[0410] In some implementations, the antibiotic may be a β-lactam antibiotic, an aminoglycoside antibiotic, a tetracycline antibiotic, a chloramphenicol antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, a quinolone antibiotic, a nitroimidazole antibiotic, a rifamycin antibiotic, an echinocandin antibiotic, a polyene antibiotic, a pyrimidine antibiotic, an allylamine antibiotic, or a azole antibiotic, or a combination thereof.

[0411] In some implementations, the antibiotic may include one or more of the following: β-lactam antibiotics, including penicillins (e.g., penicillin V), amoxicillin, ampicillin, bacancillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, pimecrolimus, pimecrolimus, ticarcillin; cephalosporins such as cefetrazol, cefadroxil, cefalexin, cefotaxime, cefotaxime, cefepime, cefepime, cefazolin, ceftriaxone, cefotaxime, cefoxitin, cefotaxime, cefotaxime, cefotaxime, cefotaxime, cefotaxime, cefotiam ... Cefuroxime, cefoxitin, cefprozil, cefuroxime, cefazolin, cefcarpine, cefodamide, cefdinir, ceftoran, cefotaxime, cefixime, cefotaxime, cefodizine, cefotaxime, cefimidazole, cefpodoxime, cefterenol, cefbuprofen, ceftiofur, cefotaxime, ceftriaxone, cefoperazone, ceftazidime, cefepime, cefrenaline, ceftiofur, cefazolin, cefepime, cefepime, ceftriaxone, cefoperazone, cefazolin, cefclorin, cefchlorazine, cefolomide, cefperazine, cefcarne, cefdrolone, cefpyridone, ceftriazole, cefvetril, cefmatine (cefmatilen), cefchlorammonium (cefme) The following antibiotics are listed: pidium, cefotaxime, cefoxitin, cefotaxime, cefoxitin, cefotaxime, thiamethoxam, monolactamase inhibitors, β-lactamase inhibitors, methicillins; aminoglycoside antibiotics, including streptomycin, gentamicin, kanamycin (e.g., kanamycin A), tobramycin, amikacin, neomycin (e.g., neomycin B, neomycin C, neomycin E), ribosomycin, simvastatin, azithromycin, dibekacin, sisomicin, netilmicin, paromomycin, brevicone, etc.; tetracycline antibiotics, including tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.; chloramphenicol antibiotics, including chloramphenicol, thiamphenicol, etc.; macrolide antibiotics. Antibiotics include: erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, midecamycin, josamycin, azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, etc.; glycopeptide antibiotics, including vancomycin, teicoplanin, etc.; quinolone antibiotics, including norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, enoxacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, including metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics, including rifampin; echinocandins; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; and azole antibiotics.Other antibiotics: fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymyxin B combinations such as polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / bacitracin, etc.

[0412] In some implementation schemes, the antibiotic may be selected from amikacin, amoxicillin, ampicillin, arsenamine, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, carbenicillin, cefaclor, cefadroxil, cephalosporin, cefalothin, cefamandole, cefazolin, cefdinir, ceftoranol, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, cefbufenozide, cefuroxime, chloramphenicol, cilastatin, clarithromycin, clavulanic acid, clindamycin, clofazimine, cloxacillin, colistin, cycloserine, dapoxetine, dapsone, dapoxetine, dicloxacillin, erythromycin, and doripenem. Doxycycline, erythromycin, ethambutol, ethionamide, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoniazid, kanamycin, lincomycin, linezolid, clocabimethionine, sulfamethoxazole, meropenem, methicillin, metronidazole, meropenem, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, oxacillin, tetracycline, paromomycin, penicillin G, penicillin V, piperacillin, acanthromycin, polymyxin B, pyrazinamide, quinupristin, rapamycin, rifabutin, rifampicin, rifapentine, rifaximin, roxithromycin Sulfadiazine, Silver Sulfadiazine, Spectinomycin, Streptomycin, Sulbactam, Sulfaacetyl, Sulfadiazine, Sulfamethoxazole, Sulfamethoxazole, Sulfamethoxazole, Sulfasalazine, Sulfaisoxazole, Tazobactam, Teicoplanin, Telavancin, Tetracycline, Temoxicillin, Tetracycline, Thiamphenicol, Ticarcillin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Acetylosin, Vancomycin, Enoxacin, Lomefloxacin, Naphazoline, Ciprofloxacin, Levofloxacin, Gatifloxacin, Moxifloxacin, Ofloxacin, Norfloxacin, Cefotetan, Cefnicillin, Cefadroxil, Cefalexin, Cephalosporin, Cephalothin, Cefmetazole, Cefotaxime, Latamoxef, Cephalosporin Pyroxime, cefuroxime aspirin, cefepime, dapavancin, demeclocycline, methacycline, ertapenem, fendamycin, gerdemycin, dextrin, posizolid, radizolid, torezolid, oritavancin, spiramycin, sulfadiazine, sulfonamidochrysoidine, gemifloxacin, naflufloxacin, trovafloxacin, grefloxacin, sparfloxacin, temafloxacin, teixobactin, melacidins, and combinations thereof.

[0413] In some implementations, antibiotics are administered in amounts that effectively kill microorganisms such as Bacillus megaterium in the subject, such as in the subject's eyes (e.g., intraocular space), blood, and / or gastrointestinal tract, such as the intestines, or inhibit their growth.

[0414] Antibiotics can be in any form, such as in the form of their corresponding pharmaceutically acceptable salts or mixtures thereof. Antibiotics can be formulated and administered according to their known routes of administration, and there are no particular limitations. In some embodiments, administration can be oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, administration is intravitreal.

[0415] Dosing regimens, such as dosage and frequency, will vary depending on a variety of factors, such as the recipient of treatment, the disease or condition being treated and its severity, the antibiotic-containing composition, the time of administration, the route of administration, the duration of treatment, the efficacy of the antibiotic, its clearance rate, and whether another drug is administered concurrently.

[0416] Exemplary alternative implementation

[0417] In some aspects, this disclosure relates to a method for establishing a model and the model established by that method. In other aspects, this disclosure discloses a method for screening drugs and drugs identified by that method. In some embodiments, this disclosure relates to the use of microorganisms in establishing models and screening drugs.

[0418] In one aspect, this document discloses a method for establishing a model, which includes infecting a model vector with a microorganism. The microorganism may include or comprise bacteria, archaea, protozoa, fungi, viruses, or combinations thereof. Preferably, the microorganism comprises bacteria, wherein the bacteria may be selected from one or more of the following: Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, and Azotobacter. The genera include *Zospira*, *Aquimarina*, *Achromobacter*, *Acidithiobacillus*, *Burkholderia*, *Marinobacter*, *Treponema*, *Actinosporangium*, *Vibrio*, *Ruminococcus*, *Methanobrevibacter*, *Shigella*, *Frankia*, *Anaeroplasma*, and *Coprococcus*.

[0419] In some preferred embodiments, the bacteria may be selected from one or more of the following: Clostridium tetanus, Clostridium perfringens, Clostridium botulinum, Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacharolytica, and Porphyromonas gingivalis. *Escherichia coli*, *Porphyromonas gingivalis*, *Campylobacter jejuni*, *Campylobacter coli*, *Campylobacter seabirds*, *Campylobacter Uppsala*, *Campylobacter concisely*, *Campylobacter fetus*, *Actinomyces israelii*, *Actinomyces naeslundii*, *Actinomyces odontolyticus*, *Escherichia coli*, *Escherichia blattae*, *Escherichia fergusonii*, *Escherichia hermannii*, *Escherichia vulneris*, *Tissierella* Klebsiella pneumoniae, Klebsiella odorata, and Azospirillum brasiliensis are all species of bacteria that have been exposed to the virus.The following bacteria are listed: *Bacillus brasiliensis*, *Achromobacter*, *Thiobacillus denitrificans*, *Thiobacillus ferrooxidans*, *Thiobacillus thiooxidans*, *Thiobacillus neapolitanus*, *Burkholderia*, *Mycobacterium marinum*, *Treponema pallidum*, *Treponema hyodysenteriae*, *Vibrio metschnikovi*, *Ruminococcus albus*, *Ruminococcus flavefaciens*, *Methanobrevibacter ruminantium*, *Shigella dysenteriae*, and *Shigella flexneri*. Shigella flexneri, Shigella boydii, Shigella sonnei, Frankiaceae, Streptomyces albus, Pseudomonas mendoza, Dermatococcus, Denitrifying Cyclophorae, Xylose-oxidizing Achromobacterium, Sphingosine sphingolipidae, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinense of alfalfa, Acidophilus ebaceae, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophaga harzianum, Bacillus licheniformis Bacillus, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter krusei, Fermentation-promoting Bacillus, Serratia marcescens, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pinnili, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvatica (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium globosum, and Corynebacterium magna.

[0420] In some preferred embodiments, the bacteria may be selected from one or more of the following: *Pseudomonas mendoza*, *Dermatococcus dermatophytes*, *Denitrifying Cyclophorae*, *Xylose-oxidizing Achromobacterium*, *Sphingosine mononitrate*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebrionella eczemae*, *Staphylococcus epidermidis*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Staphylococcus hemolyticus*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Bacillus cereus*, *Bacillus megaterium*, *Lactobacillus reuteri*, *Gardnerella vaginalis*, *Enterococcus faecalis*, *Hastyrus*. Fibriophytes, Bacillus licheniformis, Xanthomonas orientalis, Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter keloidea, fermenting paired bacilli, Serratia marcescens, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Rolstonia pinnatifida, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvatica (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium globosum, and Corynebacterium magna.

[0421] In some preferred embodiments, the bacteria are selected from one or more of the following: *Pseudomonas putida*, *Bacillus megaterium*, and *Propionibacterium acnes*. In a preferred embodiment, the bacteria is *Bacillus megaterium*.

[0422] In some preferred embodiments, this disclosure relates to a method for establishing a model of cataracts (Cat), the method comprising infecting a model vector with one or more of the following microorganisms: Pseudomonas mendoza, Coccidia dermatophytes, Cyclophila denitrificans, Achromobacter xylose oxidase, Sphingosine nigra, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinense of alfalfa, or Ebryophytes erythrosporum.

[0423] In some preferred embodiments, this disclosure relates to a method for establishing a model of age-related macular degeneration (AMD), the method comprising infecting a model vector with one or more of the following microorganisms: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophalophorae harzianum, Bacillus licheniformis, or Xanthomonas oryzae.

[0424] In some preferred embodiments, this disclosure relates to a method for establishing a model of glaucoma (GLA), the method comprising infecting a model vector with one or more of the following microorganisms: Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter krusei, fermenting paired bacilli, or Serratia marcescens.

[0425] In some preferred embodiments, this disclosure relates to a method for establishing a model of Behçet's disease (BD), the method comprising infecting a model vector with one or more of the following microorganisms: Sphingomonas vesicatoria, Klebsiella pneumoniae, Pseudomonas fluorescens, Roldstoneella pylori, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, or Subthermia sildenafil (D).

[0426] In some preferred embodiments, this disclosure relates to a method for establishing a model of Vogt-Koyanagi-Harada syndrome (VKH), the method comprising infecting a model vector with one or more microorganisms selected from Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium chrysogenum, or Corynebacterium magna.

[0427] Model carriers may include one or more of the following: humans, non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, body fluid cultures, cells, viruses, enzymes, and culture media. Non-human mammals include any mammal used for laboratory, pet, or economic purposes. Exemplary non-human mammals include mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, monkeys, or non-human primates. Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, nose, and tongue. Tissues, tissue sections, and tissue extracts include tissues, tissue sections, or tissue extracts from any part of the subject or test animal. In some embodiments, tissues include the subject's suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous body, retina, choroid, optic nerve, lens, or iris. In some embodiments, tissue extracts include DNA, RNA, or proteins. In some embodiments, body fluids include lymph, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or urine. In some implementations, the body fluid culture includes AH and VH cultures.

[0428] On the other hand, this paper discloses the use of microorganisms in establishing models, specifically, models established by infecting model vectors with microorganisms. The microorganisms and model vectors are defined as described herein.

[0429] In another aspect, this paper discloses a model established using a microbial infection model vector. The defined microorganisms and model vectors are as described herein.

[0430] In another aspect, this paper discloses a method for screening drugs, which includes (1) applying the drug to a model; and (2) analyzing the results. Preferably, the method includes: (1) establishing a model using a microbial infection model vector; (2) applying the drug to the model; and (3) analyzing the results. Drugs that kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects.

[0431] Microorganisms may include or comprise bacteria, archaea, protozoa, fungi, viruses, or combinations thereof. Preferably, the microorganisms include bacteria, wherein the bacteria may be selected from one or more of the following: Clostridium, Acinetobacter, Streptococcus, Mansonia, Fibrobacterium, Prevotella, Campylobacter, Actinomyces, Thin-layered Bacteria, Escherichia, Tylenol, Klebsiella, Porphyromonas, Azotobacter, Marine Bacteria, Achromobacter, Thiobacillus, Burkholderia, Hymenobacter, Treponema, Actinomyces sporangiosum, Vibrio, Ruminococcus, Methanobacterium, Shigella, Frankensteinia, Mycoplasma, and Stomacoccus.

[0432] In some preferred embodiments, the bacteria may be selected from one or more of the following: Clostridium tetanus, Clostridium perfringens, Clostridium botulinum, Acinetobacter acetate, Acinetobacter rufi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asacharolytica, and Porphyromonas gingivalis. *Escherichia coli*, *Porphyromonas gingivalis*, *Campylobacter jejuni*, *Campylobacter coli*, *Campylobacter seabirds*, *Campylobacter Uppsala*, *Campylobacter concisely*, *Campylobacter fetus*, *Actinomyces israelii*, *Actinomyces naeslundii*, *Actinomyces odontolyticus*, *Escherichia coli*, *Escherichia blattae*, *Escherichia fergusonii*, *Escherichia hermannii*, *Escherichia vulneris*, *Tissierella* Klebsiella pneumoniae, Klebsiella odorata, and Azospirillum brasiliensis are all species of bacteria that have been exposed to the virus.The following bacteria are listed: *Bacillus brasiliensis*, *Achromobacter*, *Thiobacillus denitrificans*, *Thiobacillus ferrooxidans*, *Thiobacillus thiooxidans*, *Thiobacillus neapolitanus*, *Burkholderia*, *Mycobacterium marinum*, *Treponema pallidum*, *Treponema hyodysenteriae*, *Vibrio metschnikovi*, *Ruminococcus albus*, *Ruminococcus flavefaciens*, *Methanobrevibacter ruminantium*, *Shigella dysenteriae*, and *Shigella flexneri*. Shigella flexneri, Shigella boydii, Shigella sonnei, Frankiaceae, Streptomyces albus, Pseudomonas mendoza, Dermatococcus, Denitrifying Cyclophorae, Xylose-oxidizing Achromobacterium, Sphingosine sphingolipidae, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinense of alfalfa, Acidophilus ebaceae, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophaga harzianum, Bacillus licheniformis Bacillus, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter krusei, Fermentation-promoting Bacillus, Serratia marcescens, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pinnili, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvatica (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium globosum, and Corynebacterium magna.

[0433] In some preferred embodiments, the bacteria may be selected from one or more of the following: *Pseudomonas mendoza*, *Dermatococcus dermatophytes*, *Denitrifying Cyclophorae*, *Xylose-oxidizing Achromobacterium*, *Sphingosine mononitrate*, *Mycobacterium abscessum*, *Arthrobacter aureus*, *Prevotella dentata*, *Rhizobium sinense*, *Ebrionella eczemae*, *Staphylococcus epidermidis*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Staphylococcus hemolyticus*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Bacillus cereus*, *Bacillus megaterium*, *Lactobacillus reuteri*, *Gardnerella vaginalis*, *Enterococcus faecalis*, *Hastyrus*. Fibriophytes, Bacillus licheniformis, Xanthomonas orientalis, Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter keloidea, fermenting paired bacilli, Serratia marcescens, Sphingosine monocytogenes, Klebsiella pneumoniae, Pseudomonas fluorescens, Rolstonia pinnatifida, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, Subthermia sylvatica (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium globosum, and Corynebacterium magna.

[0434] In some preferred embodiments, the bacteria may be selected from one or more of the following: Pseudomonas putida, Bacillus megaterium, and Propionibacterium acnes.

[0435] In a preferred embodiment, the bacteria is Bacillus megaterium.

[0436] The model carrier can be one or more of the following: human, non-human mammal, organ, tissue, tissue section, tissue extract, body fluid, body fluid culture, cell, virus, enzyme, or culture medium. Non-human mammals include any mammal for experimental, pet, or economic purposes. Exemplary non-human mammals include mice, rats, rabbits, cats, dogs, pigs, cows, bulls, sheep, goats, horses, monkeys, or non-human primates. Exemplary organs include the heart, liver, lungs, stomach, kidneys, eye, ear, nose, and tongue. Tissues, tissue sections, and tissue extracts include tissues, tissue sections, or tissue extracts from any part of the subject or test animal. In some embodiments, tissues include the subject's suspensory ligaments, ciliary body, ciliary body and ciliary muscle, vitreous body, retina, choroid, optic nerve, lens, or iris. In some embodiments, tissue extracts include DNA, RNA, or protein. In some embodiments, body fluids include lymph, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or urine. In some implementations, the body fluid culture includes AH and VH cultures.

[0437] Drugs may include one or more of the following: small molecule drugs, chemical drugs, macromolecule drugs, biological drugs, or natural drugs (traditional Chinese medicine or extracts of traditional Chinese medicine).

[0438] Preferably, the drug is effective in treating intraocular diseases or conditions including age-related macular degeneration (AMD), Behçet's disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), uveitis, retinopathy, keratoconjunctivitis sicca, sympathetic ophthalmia, trachoma, cataract (Cat), conjunctivitis, meibomian gland cysts, glaucoma (GLA), and floaters.

[0439] Chemical drugs can include: β-lactam antibiotics: penicillins, cephalosporins, β-lactamase inhibitors, and methicillin; aminoglycoside antibiotics: streptomycin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribostamycin, and neomycin; tetracycline antibiotics: tetracycline, oxytetracycline, and chlortetracycline; chloramphenicol antibiotics: chloramphenicol and thiamphenicol; macrolide antibiotics: erythromycin, leucomycin, odorless erythromycin, acetylspiramycin, midecamycin, josamycin, and azithromycin; glycopeptide antibiotics: vancomycin... Vancomycin, teicoplanin, and teicoplanin; quinolone antibiotics: norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, and gatifloxacin; nitroimidazole antibiotics: metronidazole, tinidazole, and ornidazole; rifamycin antibiotics: rifampin; echinocandins, polyenes, pyrimidines, allylamines, azoles, and other antibiotics: fosfomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, or combinations thereof.

[0440] Biopharmaceuticals can be antimicrobial peptides, which may include insect antimicrobial peptides: Lepidoptera antimicrobial peptides, Diptera antimicrobial peptides, Coleoptera antimicrobial peptides, Hymenoptera antimicrobial peptides, and silkworm antimicrobial peptides; mammalian antimicrobial peptides: porcine antimicrobial peptides, sheep antimicrobial peptides, bovine antimicrobial peptides, and human antimicrobial peptides; amphibian antimicrobial peptides: African clawed frog; antimicrobial peptides derived from fish, mollusks, or crustaceans: leopard antimicrobial peptides, mussel antimicrobial peptides, and shrimp antimicrobial peptides; bacterial antimicrobial peptides: bacitracin, brevicin, polymyxin, and nisin; plant antimicrobial peptides, or combinations thereof.

[0441] Natural medicinal herbs may include: Astragalus membranaceus, Polygonatum sibiricum, Angelica sinensis, Panax notoginseng, Rhizoma Imperatae, Rhubarb Charcoal, Curcuma aromatica, Fritillary bulb, Coix seed, Pinellia ternata, Calcine dancient ink, Salvia miltiorrhiza, Arnebia euchroma, Radix Isatidis, Houttuynia cordata, Honeysuckle, Rhizoma Coptis, Scutellaria baicalensis, Dandelion, Purslane, Hawthorn, Isatidis Folium, Forsythia suspensa, and Herba Artemisiae. Capillaris, Andrographis Paniculata Nees, Bupleurum chinense, Rhubarb, Euphorbia humifusa, Stemonae, Garlic, Cortex Phellodendri, Eucommia ulmoides, Cortex Fraxini, Fructus Cnidii, Galla chinensis, Viola yedoensis makino, Fructus Mume, Radix Glycyrrhizae, Pericarpium Granati, Schisandra chinensis, Spina Gleditsiae, Terminalia chebula, Sophora flavescens, Cortex Pseudolaricis, Epimedium, Artemisia apiacea Hance), their extracts, or combinations thereof.

[0442] The drugs disclosed herein may be oral drugs, injectable drugs, or topical drugs, and topical drugs include mucosal drugs, preferably ocular drugs.

[0443] The medicaments disclosed herein may be in the form of solutions, tablets, pills, capsules, injections, powders, powders for injection, patches, coatings, or mucosal application preparations, preferably eye drops, ointments, or eye sprays.

[0444] In some preferred embodiments, this disclosure relates to a method for screening drugs for treating or preventing cataracts (Cat), the steps of which are as follows:

[0445] (1) Use one or more of the following microbial infection model vectors to establish a model: Pseudomonas mendoza, Coccidia dermatoides, Cyclophila denitrified, Achromobacter xylose oxidizing, Sphingosine japonicus, Mycobacterium abscessus, Arthroblastus aureus, Prevotella dentata, Rhizobium sinense of alfalfa or Acidobacter erythrosporum.

[0446] (2) Applying drugs to the model;

[0447] (3) Analysis results. Drugs that can kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects on Cat patients.

[0448] In some preferred embodiments, this disclosure relates to a method for screening drugs for the treatment or prevention of age-related macular degeneration (AMD), the method comprising the following steps:

[0449] (1) Use one or more of the following microbial infection model vectors to establish a model: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis or Xanthomonas oryzae;

[0450] (2) Applying drugs to the model;

[0451] (3) Analysis results. Drugs that can kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects on AMD patients.

[0452] In some preferred embodiments, this disclosure relates to a method for screening drugs for the treatment or prevention of glaucoma (GLA), the steps of which are as follows:

[0453] (1) Use one or more of the following microbial infection model vectors to establish a model: Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas testis, Mycobacterium kansas, Bacillus thuringiensis, Citrobacter kurstii, fermenting paired bacilli or Serratia marcescens.

[0454] (2) Applying drugs to the model;

[0455] (3) Analysis results. Drugs that can kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects on GLA patients.

[0456] In some preferred embodiments, this disclosure relates to a method for screening drugs for the treatment or prevention of Behçet's disease (BD), the steps of which are as follows:

[0457] (1) Use one or more of the following microbial infection model vectors to establish a model: Sphingomonas vesiculosus, Klebsiella pneumoniae, Pseudomonas fluorescens, Roldstone bacillus piscini, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii or Subthermia sildenafil (D).

[0458] (2) Applying drugs to the model;

[0459] (3) Analysis results. Drugs that can kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects on BD patients.

[0460] In some preferred embodiments, this disclosure relates to a method for screening drugs for the treatment or prevention of Vogt-Koyanagi-Harada syndrome (VKH), the method comprising the following steps:

[0461] (1) Use one or more of the following microbial infection model vectors to establish a model: Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium globosum or Corynebacterium gravidarum;

[0462] (2) Applying drugs to the model;

[0463] (3) Analysis results. Drugs that can kill or inhibit microorganisms in the model can be identified as having therapeutic or preventive effects on VKH patients.

[0464] On another front, this paper discloses the use of microorganisms in drug screening. Specifically, the steps for drug screening are as follows: establishing a model by infecting a model vector with a microorganism; applying the drug to the model; and screening the therapeutic or preventive effects of the drug. The scope of microorganisms, model vectors, and drugs is defined as described above.

[0465] In another aspect, this paper discloses a drug identified through the following steps: establishing a model by infecting a microbial model vector; applying the drug to the model; and screening for positive drug results. The definitions of microorganism, model vector, and drug are as described above.

[0466] A positive result means that the identified drug can kill or inhibit microorganisms in the model.

[0467] Exemplary Implementation Schemes 1-25

[0468] Implementation Scheme 1. A method for establishing an intraocular disease or symptom model, the method comprising using a microbial infection model vector.

[0469] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the microorganism includes bacteria, archaea, protozoa, fungi, viruses, or combinations thereof.

[0470] Implementation Scheme 3. The method according to Implementation Scheme 1, wherein the model carrier includes one or more of the following: human, non-human mammal, organ, tissue, tissue section, tissue extract, body fluid, body fluid culture, cell, virus, enzyme, and culture medium.

[0471] Implementation Scheme 4. The method according to Implementation Scheme 2, wherein the microorganism comprises bacteria selected from one or more of the following: Clostridium, Acinetobacter, Streptococcus, Mansonia, Fibrobacterium, Prevotella, Campylobacter, Actinomyces, Thin-layered Bacteria, Escherichia, Tylenol, Klebsiella, Porphyromonas, Azotobacter, Marine Bacteria, Achromobacter, Thiobacillus, Burkholderia, Hymenobacter, Treponema, Actinomyces sporangiosum, Vibrio, Ruminococcus, Methanobacterium, Shigella, Frankensteinia, Mycoplasma, and Styracaceae.

[0472] Implementation Scheme 5. The method according to Implementation Scheme 4, wherein the bacteria are selected from one or more of the following: Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calciacetate, Acinetobacter ruffi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter jumbo, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, non-glycolytic porphyromonas, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter seabird, Campylobacter uppsala, Campylobacter conjugate, Campylobacter fetus, and Campylobacter erythropoietin. Actinomycetes, Neisseria gonorrhoeae, Actinomyces dentata, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Tyrobacterium salina, Klebsiella pneumoniae, Klebsiella odorifera, Achromobacterium, Thiobacillus denitrification, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus naplesii, Burkholderia, Mycobacterium marineum, Treponema pallidum, Treponema swine dysentery, Vibrio medroxypenaeus, Rumenococcus albus, Rumenococcus xanthophyllus, Shorter bacilli methanogene, Shigella dysenteriae, Shigella flexneri, Shigella boulardii Shigella sonnei, Frankelbrium, Streptomyces albopictus, Pseudomonas mendoza, Dermatophytes, Denitrifying Cyclophorae, Xylose-oxidizing Achromobacterium, Sphingosine japonicum, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinusoids of alfalfa, Acidophilus ebaceae, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophaga harzianum *Vitamin Bacillus*, *Bacillus licheniformis*, *Xanthomonas oryzae*, *Acinetobacter baumannii*, *Acinetobacter calcareae*, *Trichomonas testis*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter keloidea*, *Bacillus fermentum*, *Serratia marcescens*, *Sphingosoma viride*, *Klebsiella pneumoniae*, *Pseudomonas fluorescens*, *Rolstonia pinnatifida*, *Lactobacillus curvularia*, *Burkholderia polyphaga*, *Lactobacillus delbrueckii*, *Subthermia sylvatica* (D), *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Goldenbacterium gravidum*.

[0473] Implementation Scheme 6. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is selected from cataracts, age-related macular degeneration, glaucoma, Behçet's disease, Vogt-Koyanagi-Harada syndrome, or uveitis.

[0474] Implementation Scheme 7. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is cataract, wherein the method includes using a microbial infection model vector selected from one or more of the following: Pseudomonas mendoza, dermatophytes, denitrifying lipophilic bacteria, xylose-oxidizing achromobacterium, sphingosine nigra, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinense of alfalfa, or Ebryophyte erythritolone.

[0475] Implementation Scheme 8. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is age-related macular degeneration, wherein the method includes using a microbial infection model vector selected from one or more of the following: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, or Xanthomonas oryzae.

[0476] Implementation Scheme 9. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is glaucoma, wherein the method includes using a microbial infection model vector selected from one or more of the following: Acinetobacter baumannii, Acinetobacter calcium acetate, Trichomonas vaginalis, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter krusei, fermenting protozoa, or Serratia marcescens.

[0477] Implementation Scheme 10. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is Behcet's disease, wherein the method includes using a microbial infection model vector selected from one or more of the following: Sphingomonas vesicatoria, Klebsiella pneumoniae, Pseudomonas fluorescens, Roldstoneella picelli, Lactobacillus curvularia, Burkholderia polyphaga, Lactobacillus delbrueckii, or Subthermia sildenafil (D).

[0478] Implementation Scheme 11. The method according to Implementation Scheme 1, wherein the intraocular disease or condition is Vogt-Koyanagi-Harada syndrome, wherein the method includes using a microbial infection model vector selected from one or more of the following: Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium chrysogenum, or Corynebacterium magna.

[0479] Implementation Plan 12. Use of microorganisms in establishing models of intraocular diseases or symptoms.

[0480] Implementation Scheme 13. An eye disease model, said model being generated by the method according to Implementation Scheme 1.

[0481] Implementation Scheme 14. Use of microorganisms in the creation of models for screening drugs for eye diseases.

[0482] Implementation Scheme 15. The use according to Implementation Scheme 14, wherein the drug comprises one or more of a chemical drug, a biological drug, or a natural drug.

[0483] Implementation Scheme 16. The use according to Implementation Scheme 15, wherein the chemical drug comprises β-lactam antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, chloramphenicol antibiotics, macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics, rifamycin antibiotics, echinocandins, polyene antibiotics, pyrimidine antibiotics, allylamine antibiotics, azole antibiotics, and other antibiotics or combinations thereof.

[0484] Implementation Scheme 17. The use according to Implementation Scheme 15, wherein the biopharmaceutical is an antimicrobial peptide.

[0485] Implementation Scheme 18. The use according to Implementation Scheme 15, wherein the natural medicine comprises Astragalus membranaceus, Polygonatum sibiricum, Angelica sinensis, Panax notoginseng, Imperata cylindrica, Rheum palmatum (charred), Curcuma longa, Fritillaria cirrhosa, Coix lacryma-jobi, Pinellia ternata, calcined ink, Salvia miltiorrhiza, Lithospermum erythrorhizon, Isatis indigotica, Houttuynia cordata, Lonicera japonica, Coptis chinensis, Scutellaria baicalensis, Taraxacum mongolicum, Portulaca oleracea, Crataegus pinnatifida, Isatis tinctoria, Forsythia suspensa, Artemisia capillaris, Andrographis paniculata, Bupleurum chinense, Rheum palmatum, Euphorbia humifusa, Stemona japonica, Garlic, Phellodendron chinense, Eucommia ulmoides, Fraxinus chinensis, Cnidium monnieri, Galla chinensis, Viola yedoensis, Prunus mume, Glycyrrhiza uralensis, Punica granatum peel, Schisandra chinensis, Gleditsia sinensis thorns, Terminalia chebula, Sophora flavescens, Pseudolarix amabilis bark, Epimedium brevicornu, Artemisia annua, extracts thereof, or combinations thereof.

[0486] Implementation Scheme 19. The use according to Implementation Scheme 14, wherein the microorganism includes bacteria, archaea, protozoa, fungi, viruses, or combinations thereof.

[0487] Implementation Scheme 20. The use according to Implementation Scheme 19, wherein the microorganism comprises bacteria selected from one or more of the following: Clostridium, Acinetobacter, Streptococcus, Mansonia, Fibrobacterium, Prevotella, Campylobacter, Actinomyces, Thin-layered Bacteria, Escherichia, Tylenol, Klebsiella, Porphyromonas, Azotobacter, Marine Bacteria, Achromobacter, Thiobacillus, Burkholderia, Hymenobacter, Treponema, Actinomyces sporangiosum, Vibrio, Ruminococcus, Methanobacterium, Shigella, Frankensteinia, Mycoplasma, and Styracaceae.

[0488] Implementation Scheme 21. According to the use described in Implementation Scheme 20, wherein the bacteria are selected from one or more of the following: Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calciacetate, Acinetobacter ruffi, Acinetobacter baumannii, Acinetobacter hemolyticus, Acinetobacter jumbo, Acinetobacter johnsonii, Streptococcus pyogenes, hemolytic streptococci, non-glycolytic porphyromonas, Porphyromonas gingivalis, Campylobacter jejuni, Campylobacter coli, Campylobacter salina, Campylobacter uppsala, Campylobacter conjugate, Campylobacter fetus, Actinomyces ylangis, Actinomyces nepenthes, Actinomyces dentiformis, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Escherichia coli, Typha nauplii, Typha nauplii, Mycobacterium marinum, Treponema pallidum, Treponema swine dysentery, Vibrio medroxypenaeus, Rumenococcus albus, Rumenococcus faecalis, Methanobacterium rumenans, Shigella dysenteriae, Shigella flexneri, Shigella boulardii Shigella sonnei, Frankeldae, Streptomyces albopictus, Pseudomonas mendozae, Dermatococcus, Denitrifying Cyclophorae, Xylose-oxidizing Achromobacterium, Sphingosine japonicus, Mycobacterium abscessum, Arthrobacter aureus, Prevotella dentata, Rhizobium sinusoids of alfalfa, Acidophilus ebaceae, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibrophaga harzianum *Vitamin Bacillus*, *Bacillus licheniformis*, *Xanthomonas oryzae*, *Acinetobacter baumannii*, *Acinetobacter calcareae*, *Trichomonas testis*, *Mycobacterium kansasense*, *Bacillus thuringiensis*, *Citrobacter keloidea*, *Bacillus fermentum*, *Serratia marcescens*, *Sphingosoma viride*, *Klebsiella pneumoniae*, *Pseudomonas fluorescens*, *Rolstonia pinnatifida*, *Lactobacillus curvularia*, *Burkholderia polyphaga*, *Lactobacillus delbrueckii*, *Subthermia sylvatica* (D), *Escherichia coli*, *Micrococcus luteus*, *Bacillus subtilis*, *Corynebacterium globosum*, *Goldenbacterium gravidum*.

[0489] Implementation Scheme 22. The use according to Implementation Scheme 14, wherein the eye disease is selected from cataracts, age-related macular degeneration, glaucoma, Behçet's disease, Vogt-Koyanagi-Harada syndrome, or uveitis.

[0490] Implementation Scheme 23. A method for screening drugs, the method comprising: (1) applying the drug to a model according to Implementation Scheme 13; and (2) analyzing the results.

[0491] Implementation Scheme 24. The method according to Implementation Scheme 23, wherein the drug comprises one or more of a chemical drug, a biological drug, or a natural drug.

[0492] Implementation Scheme 25. A medicament identified by the method according to Implementation Scheme 23.

[0493] Additional exemplary embodiments B1-B104

[0494] This disclosure also provides the following additional exemplary embodiments B1-B104.

[0495] Implementation Scheme B1. A method for treating or preventing age-related macular degeneration (AMD) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt or ester thereof:

[0496]

[0497] in:

[0498] Cy 1 and Cy 2 Each is independently an optionally substituted cycloalkyl ring (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 3-7 Cycloalkyl rings), optionally substituted heterocycles (e.g., 4-7 membered heterocycles), optionally substituted aryl rings (e.g., C14-C24-C1 ... 6-10 Aryl rings) or optionally substituted heteroaromatic rings (e.g., 5-10 nucleotide heteroaromatic rings);

[0499] L and L' are each independently an empty or connecting base;

[0500] L 2 It is an empty, optional substitution of C. 1-6 Alkylene, optionally substituted C 1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-6 Cycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or optionally substituted 4-7 membered heterocycloalkylene,

[0501] W is - OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO2NR 3c R 4c ;-OSO2NR 3d R4d ;-SR 5 ;-SO2R 5a ;-OCOR 2a -OSO2R 5a or

[0502] in:

[0503] R 1 and R 1a Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic.

[0504] R 3 and R 4 Each is independently hydrogen, -COR 2b -SO2R 5b Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic, or R 3 and R 4 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups;

[0505] R 2 R 2a R 2b R 5 R 5a and R 5b Each is independently hydrogen, -OH, -NR 3e R 4e Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic groups; and

[0506] R 3a R 3b R 3c R 3d R 3e R 4a R 4b R4c R 4d and R 4e Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optional C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or 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 Together with the atoms they bind to, they form optionally substituted 4-7 membered heterocyclic groups.

[0507] Implementation Scheme B2. The method according to Implementation Scheme B1, wherein in Formula I, Cy 1 and Cy 2 At least one of them is an optional substitution of C. 6-10 Aryl ring or optionally substituted 5-10 member heteroaryl ring.

[0508] Implementation Scheme B3. The method according to Implementation Scheme B1, wherein the compound of Formula I has Formula I-1:

[0509]

[0510] Among them, Ar 1 and Ar 2 Each is an optional substitution of C. 6-10 Aryl ring or optionally substituted 5-10 membered heteroaromatic ring. Embodiment B4. The method according to Embodiment B3, wherein Ar in Formula I-1 1 and Ar 2 Each is independently a substituted phenyl ring or a substituted 5- or 6-membered heteroaromatic ring.

[0511] Implementation Scheme B5. The method according to Implementation Scheme B3, wherein Ar in formula I-1 1 and Ar 2 Each of them independently is an optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring.

[0512] Implementation Scheme B6. The method according to Implementation Scheme B1, wherein the compound of Formula I has Formula I-2:

[0513]

[0514] in:

[0515] m is 0, 1, 2, or 3.

[0516] R 10 Each time it appears, it is independently halogen, -L 2’ -W', optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 10 Or an R 10 Together with L or L' and the atoms to which they are bonded, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0517] Where L 2’ And W' respectively have L 2 And W as defined in implementation scheme B1, and -L 2’ -W' is selected independently each time it appears.

[0518] Implementation Scheme B7. The method according to Implementation Scheme B6, wherein Cy in formula I-2 1 It is an optionally substituted phenyl ring, an optionally substituted thiophene ring, an optionally substituted furanyl ring, an optionally substituted pyridyl ring, or an optionally substituted pyrimidinyl ring.

[0519] Implementation Scheme B8. The method according to Implementation Scheme B6, wherein Cy in formula I-2 1 C is an optional substitute 3-6 A cycloalkyl ring or optionally substituted 4-7 heterocycle, the heterocycle having one or two cyclic heteroatoms independently selected from N, O and S.

[0520] Implementation Scheme B9. The method according to Implementation Scheme B6, wherein the compound of Formula I-2 has Formula I-3:

[0521]

[0522] in:

[0523] n is 0, 1, 2, or 3.

[0524] R 11 Each time it appears, it is independently halogen, -L 2’ -W', optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group; or two adjacent R groups 11 Or an R 11 Together with L or L' and the atoms to which they are bonded, they form optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings;

[0525] Where L 2’ And W' respectively have L 2 And W as defined in implementation scheme B1, and -L 2’ -W' is selected independently each time it appears.

[0526] Implementation Scheme B10. The method according to any one of Implementation Schemes B1-9, wherein L and L' in Formula I are each independently empty, -C(O)-, or optionally substituted C. 1-4 Alkylene, optionally substituted C 2-4 -olefin, -O-, -S-, -NR 100 -、-S(O)-、-SO2-、-X 1 -G 1 -、-X 2 -G 2 -X 2a -or-CR 101 R 102 -,

[0527] in:

[0528] X 1 X 2 and X 2a C is independently optional substitution 1-4 Alkylene, optionally substituted C 2-4 -olefin, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0529] G 1 and G 2 C is independently optional substitution1-4 Alkylene, optionally substituted C 2-4 alkenyl, -C(O)-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;

[0530] The prerequisite is -X 1 -G 1 -or-X 2 -G 2 -X 2a -Does not contain ON, SS, SN (except SO2-N) or -C(O)-S bonds;

[0531] R 100 and R 100a Each is an isolated pair (where applicable), hydrogen, COR 2c -SO2R 5c Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic; or R 100 or R 100a With R 10 or R 11 The groups form optionally substituted heterocyclic or heteroaryl rings;

[0532] R 101 R 101a R 102 and R 102a Each is independently a hydrogen, -OH, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkoxy, optionally substituted amino group, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocyclic group, or R 101 and R 102 、or R 101a and R 102a Together with the atoms they are bonded to, they form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; or R 101 and R 102 One of them, or R 101a and R 102a One of them and R10 or R 11 The groups together form an optionally substituted cycloalkyl or heterocyclic ring; and

[0533] R 2c and R 5c Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Cycloalkoxy, optionally substituted phenyl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted 4- to 7-membered heterocyclic group.

[0534] Implementation Scheme B11. The method according to Implementation Scheme B10, wherein L and L' in Formula I are each independently empty, -O-, -C(O)-, -S-, -NR 100 -、-S(O)-、-SO2- or -CR 101 R 102 -

[0535] Implementation Scheme B12. The method according to Implementation Scheme B10, wherein the compound of Formula I has a formula according to any one of I-4 to I-5:

[0536]

[0537] in:

[0538] X 3 X 4 and X 5 Each of these can be independently: empty, -O-, -C(O)-, -S-, -NR 100a -、-S(O)-、-SO2- or -CR 101a R 102a -;as well as

[0539] R 10 R 11 R 100a R 101a R 102a W, L 2 m and n are defined above.

[0540] Implementation Scheme B13. The method according to any one of Implementation Schemes B1-12, wherein L in Formula I 2 It is empty.

[0541] Implementation Scheme B14. The method according to any one of Implementation Schemes B1-12, wherein L in Formula I2 and each L 2’ The instance is independently empty, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene.

[0542] Implementation Scheme B15. The method according to any one of Implementation Schemes B1-14, wherein W in Formula I and each W ’ The instances are independently –OH, -NH2, -SO2NH2, -SO2NH(C) 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C 1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 Alkyl, -OH, -NH2 and fluorine are substituted.

[0543] Implementation Scheme B16. The method according to any one of Implementation Schemes B1-15, wherein W in Formula I is –OH, -NH2, -SO2NH2, -SO2NH (acetyl), -COOH, Or -OC(O)-CH3.

[0544] Implementation Scheme B17. The method according to any one of Implementation Schemes B12-16, wherein the compound has formula I-4 or I-5,

[0545] in:

[0546] L 2 and each L 2 'The instance is empty,'

[0547] W and each W' instance are independently –OH, -NH2, -SO2NH2, -SO2NH(C) 1-4 alkyl), -SO2NH(C 1-4 alkyl acyl group), -COOH, -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl), -OC(O)NH2, -OC(O)NH(C1-4 Alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 Alkyl), wherein each C 1-4 Alkyl groups are independently selected from C10. 1-4 Alkyl, C 1-4 Alkyl, -OH, -NH2, and 1-3 fluorine substituents are used for substitution;

[0548] R 10 and R 11 Each of these elements, when it appears, is independently F; Cl; –OH; -NH2; -SO2NH2; -SO2NH(C) 1-4 Alkyl); -SO2NH(C 1-4 Alkyl group); -C(O)(OC 1-10 Alkyl), -C(O)(OC 2-10 alkenyl); -COOH; -OC(O)NH2;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Alkyl); optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkenyl; optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 2-6 Alkyne group; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 cycloalkyl; optionally independently selected from C 1-4 alkyl and fluorine 1-3 substituents of C 3-6 Cycloalkoxy; or optionally independently selected from C 1-4 Alkyl, C 1-4 C with 1-3 substituents of alkoxy, -OH, -NH2 and fluorine 1-4 Alkoxy group; and m is 0, 1 or 2, and n is 0, 1, 2 or 3.

[0549] Implementation Scheme B18. The method according to Implementation Scheme B17, wherein the compound has formula I-4, wherein X 3 and X 4Each is independently -O-, -C(O)-, -S-, -NR 100a -or -SO2-.

[0550] Implementation Scheme B19. The method according to Implementation Scheme B17, wherein the compound has formula I-5, wherein X 5 It is -O-, -C(O)-, -S-, -NR 100a -or -SO2-.

[0551] Implementation Scheme B20. The method according to Implementation Scheme B18 or 19, wherein the compound has formula I-4 or I-5, wherein R 100a It is hydrogen or an optional substituted C 1-4 alkyl.

[0552] Implementation Scheme B21. The method according to any one of Implementation Schemes B1-20, wherein the compound of Formula I or its pharmaceutically acceptable salt or its ester is in an isolated or substantially purified form.

[0553] Implementation Scheme B22. A method for treating or preventing age-related macular degeneration (AMD) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt or ester thereof:

[0554] Cy 10 ——L 10 ——cy 11 -L 11 -W 10

[0555] Formula II

[0556] in:

[0557] Cy 10 and Cy 11 Each is independently an optionally substituted cycloalkyl ring (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 3-7 Cycloalkyl rings), optionally substituted heterocycles (e.g., 4-7 membered heterocycles), optionally substituted aryl rings (e.g., C14-C24-C1 ... 6-10 Aryl ring), optionally substituted heteroaromatic ring (e.g., 5-10 membered heteroaromatic ring), or optionally substituted ring structure comprising a cycloalkyl ring or heterocyclic ring and an aryl or heteroaromatic ring, wherein the ring structure may be a fused ring;

[0558] L 10 It is an empty or connecting base;

[0559] L 11 It is an empty, optional substitution of C. 1-6 Alkylene, optionally substituted C1-6 Heteroalkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substit...

Claims

1. The use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for the treatment or prevention of age-related macular degeneration (AMD) in a subject of need, wherein said compound has the following chemical structure: 。 2. The use according to claim 1, wherein the subject is identified as infected with a microorganism.

3. The use according to claim 1, wherein the subject is identified as having a microbial infection in the intraocular space.

4. The use according to claim 2, wherein the microorganism comprises Bacillus megaterium.

5. The use according to claim 2, wherein the microorganism comprises one or more selected from the following: Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus hemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecalis, Fibroblastus harzianum, Bacillus licheniformis, and Xanthomonas oryzae.

6. The use according to any one of claims 1-5, wherein the compound or a pharmaceutically acceptable salt or ester thereof or the pharmaceutical composition is administered to the subject in an amount that effectively kills or inhibits the growth of the microorganisms in the subject's eyes, blood, and / or gastrointestinal tract.

7. The use according to claim 1, wherein the compound or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition thereof, is administered to the subject in an amount that effectively kills or inhibits the growth of the microorganisms in the subject's intraocular space, blood, and / or intestine.

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

9. The use according to any one of claims 1-5, wherein the pharmaceutical composition is administered topically, intravitreally, intramuscularly, subcutaneously, or intravenously.

10. The use according to any one of claims 1-5, wherein the pharmaceutical composition further comprises an antibiotic and / or an anti-VEGF drug.

11. The use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for use in subjects in need of killing or inhibiting the growth of Bacillus megaterium, for treating Bacillus megaterium infection, wherein said compound has the following chemical structure: 。 12. The use according to claim 11, wherein the megaterium infection is an ocular megaterium infection of the subject.

13. The use according to claim 11, wherein the *Bacillus megaterium* infection is a *Bacillus megaterium* infection in the intraocular space of the subject.

14. The use according to claim 11, wherein the subject has AMD, or does not have AMD, or is at risk of developing AMD.

15. The use according to any one of claims 11-14, wherein the pharmaceutical composition further comprises an antibiotic and / or an anti-VEGF drug.

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