Antibacterial composition

Abstract

The present disclosure relates to organosulfur compounds and compositions containing the same. In particular, the disclosure relates to bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate. Such compositions are useful for treating microbial infections, particularly bacterial, fungal, protozoan, or algal infections. Compositions containing the compounds are also useful for cleaning, disinfecting, or agricultural applications.

Description

[Technical Field]

[0001] The present disclosure relates to organosulfur compounds and compositions containing the same. In particular, the disclosure relates to bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate. Such compositions are useful for treating microbial infections, particularly bacterial, fungal, protozoan, or algal infections. Compositions containing the compounds are also useful for cleaning, disinfecting, or agricultural applications. [Background technology]

[0002] Microorganisms, such as bacteria and fungi, are found almost everywhere and exist in a wide variety of forms. Most are not harmful and are, in fact, essential to life on Earth and the health of plants, animals, and humans. For example, the microbiome in the intestines of humans and animals, where bacteria and fungi live as symbiotic organisms with their hosts, is known as the gut microbiota. Bacteria also naturally reside on the skin, where they form part of the immune system. Another example is soil biology, which is largely composed of bacteria and fungi, as well as protozoa. Another example is aquatic biology and wastewater treatment, where protozoa play an important role in improving water clarity. Some bacteria, fungi (including yeasts), protozoa, and algae can cause pathogenic infections, for example, in animals or humans. These pathological infections can lead to illness and disease in infected individuals. Plants are also susceptible to microbial infections.

[0003] Thus, there is a need for antibacterial compounds as well as alternative treatments for microbial infections. Summary of the Invention

[0004] The present disclosure provides the following preferred embodiments. 1. A compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one such compound, for use in the treatment or prevention of a microbial infection, preferably a bacterial or fungal infection. 2. A method of treating or preventing a microbial infection in an individual, comprising administering to an individual in need thereof a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds. 3. A composition comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, wherein the composition is a pharmaceutical composition, an agricultural chemical, or a food composition. 4. An article having a surface at least partially coated with a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one such compound, preferably wherein the article is a medical device or a surgical device. 5. (i) a compound selected from bis(4-fluorophenyl) disulfide, bis(4-chlorophenyl) disulfide, bis(4-chlorophenyl) thiosulfinate, bis(4-fluorophenyl) thiosulfinate, bis(4-chlorophenyl) thiosulfonate, bis(4-fluorophenyl) thiosulfonate, and di-isopropyl thiosulfonate; (ii) a surfactant. 6. An in vitro method comprising applying a cleaning or disinfecting composition to a surface, wherein the composition comprises a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate. 7. The method of embodiment 6, wherein the method is a method of sanitizing or disinfecting the surface. 8. Use of a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, as a disinfectant, sanitizer, or antimicrobial agent in food. 9. A cleaning or disinfecting product comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one such compound. 10. An agricultural composition comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, and an agriculturally acceptable excipient, carrier, and / or solvent. 11. A method for preventing or treating an infection on a plant or plant part, comprising contacting the plant or plant part with a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, such that the infection is prevented or treated. 12. Use of a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, for preventing or treating infections on plants or plant parts. 13. The use or method of embodiment 11 or 12, wherein the compound or composition is applied directly to the plant, to the seeds of the plant, or to the soil of the plant or seeds. 14. The use or method of any of embodiments 11-13, wherein the plant is selected from the group consisting of Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, and Brassicaceae, preferably the plant is selected from the group consisting of Begonia, tomato, potato, sugar beet, strawberry, cabbage, apple, Orchidaceae, Chrysanthemum, Fabaceae, Cucurbitaceae, Pisum, Vitis, Vaccinia, and Lactuca. [Brief explanation of the drawings]

[0005] [Figure 1] Average MIC90 values ​​per strain per compound. Values ​​were determined during the MIC assay and then averaged for each strain. Each data point represents the average MIC90 for each strain. Data points are labeled as follows: E. coli = Ec, K. pneumoniae = Kp, S. agalatiae = Sag, L. garvieae = Lg, S. uberis = Su, S. suis = Ss, S. aureus = Sau, A. baumannii = Ab, M. lutues = Ml, S. epidermidis = Se, P. aeruginosa = Pa, M. viscosa = MV, and C. albicans = Ca. For bis-4-chlorophenyl disulfide and Lg, Kp, Su, Sag, Ec, Ss, Sau, and Ab, the MIC90 is expressed as 1000 μM but is actually greater than 1000 μM because no MIC90 values ​​were detected within the range tested. The same applies to Pa, Ab, Kp, Ec, and Lg for bis-(4-fluorophenyl)-disulfide, but then the true MIC90 values ​​are above 4000 μM, and for bis-(4-chlorophenyl)thiosulfonate, as well as Ec, Kp, and Ab, the MIC90 values ​​are above 1000 μM. [Figure 2] Figure 1 presents the cytotoxic effect of the emulsifiers Tween-80 and DMSO at the concentrations used, without antimicrobial (AM) compounds, on the Caco-2 cell line. [Figure 3]Figure 1 presents the cytotoxic effect of the emulsifiers Tween-80 and DMSO at the concentrations used, without antimicrobial (AM) compounds, on the HepG2 cell line. [Figure 4] Cytotoxic effect of emulsified AM2 on Caco-2 cells. [Figure 5] Cytotoxic effect of emulsified AM2 on HepG2 cells. [Figure 6] Cytotoxic effect of emulsified AM3 on Caco-2 cells. [Figure 7] Cytotoxic effect of emulsified AM3 on HepG2 cells. [Figure 8] Cytotoxic effect of emulsified AM6 on Caco-2 cells. [Figure 9] Cytotoxic effect of emulsified AM6 on HepG2 cells. [Figure 10] Cytotoxic effect of emulsified AM8-A on Caco-2 cells. AM8-A was emulsified with 30-fold less Tween 80 and no DMSO was added. [Figure 11] Cytotoxic effect of emulsified AM8-A on HepG2 cells. AM8-A was emulsified with 30-fold less Tween 80 and no DMSO was added. [Figure 12] Cytotoxic effect of emulsified AM8-C on Caco-2 cells. AM8-C was emulsified with 30-fold less Tween 80 and no DMSO was added. [Figure 13] Cytotoxic effect of emulsified AM8-C on HepG2 cells. AM8-C was emulsified with 30-fold less Tween 80 and no DMSO was added. [Figure 14] Colony diameters of the tested fungus Pythium aphanidermatum after 7 days of incubation with AM2, bis(p-chlorophenyl) disulfide; AM3, bis(p-fluorophenyl) disulfide; AM6, bis(p-chlorophenyl) thiosulfonate; AM8, bis(isopropyl) thiosulfonate, and QQ2, diisopropyl thiosulfonate. Larger colony diameters indicated less growth inhibition. [Figure 15]Colony diameter of the tested fungus Phytophtora cinnamiomi after 7 days of incubation with AM2, AM3, AM6, AM8, and QQ2. [Figure 16] Colony diameter of the tested fungus Fusarium oxysporum after 7 days of incubation with AM2, AM3, AM6, AM8, and QQ2. [Figure 17] Colony diameter of the tested fungus Sclerotinia sclerotiorum after 7 days of incubation with AM2, AM3, AM6, AM8, and QQ2. [Figure 18] Colony diameter of the tested fungus Rhizoctonia solani after 7 days of incubation with AM2, AM3, AM6, AM8, and QQ2. [Figure 19] Colony diameter of the tested fungus Botrytis cinerea after 7 days of incubation with AM2, AM3, AM6, AM8, and QQ2. [Figure 20] Raw data of colony diameter 3 days after inoculation. [Figure 21] Raw data of colony diameter 7 days after inoculation. [Figure 22] Raw data of colony diameter 10 days after inoculation. [Figure 23] Raw data of colony diameter 14 days after inoculation. [Figure 24] Effect of daily exposure to AM-8 on AMR Staphylococcus aureus in mature biofilms: Seven-day-old mature Staphylococcus aureus LUH14616 biofilms in 96-well polystyrene plates were exposed daily for up to 4 days to various concentrations of AM-8 prepared in PBS containing 2% v / v BHI, or its diluent (1% DMSO) as a control. Each day, the number of viable bacteria within the biofilms was microbiologically enumerated. [Figure 25]Effect of AM-2 and AM-8 on AMR Staphylococcus aureus persisters: Seven-day-matured S. aureus LUH14616 biofilms were exposed daily for three days to 10x minimum bactericidal concentrations (MBC) of rifampicin and ciprofloxacin. Biofilms were then exposed to various concentrations of AM-2 or AM-8 for 24 hours, or to 10x MBC rifampicin / ciprofloxacin (to demonstrate antibiotic tolerance of persisters). Experiments were performed in triplicate. [Figure 26] AM-8 induces little or no resistance in AMR S. aureus LUH14616. Staphylococcus aureus LUH146161 was exposed to a range of subsequent AM-8 concentrations. For this purpose, two independently synthesized batches of AM-8 were used with a minimum purity of 96.3%. A total of 19 passages were performed. As a control, S. aureus LUH14616 was exposed to a range of rifampicin doses, and when resistance emerged, it was exposed to a range of adjusted concentrations of the antibiotic, as shown above for AM-8. Results are expressed as fold increases, i.e., the ratio of the MIC after various passages to the MIC at the start of the experiment. The graphs show matching circles and squares.

[0006] AM2 = bis(4-chlorophenyl) disulfide AM3 = bis(4-fluorophenyl) disulfide AM6 = bis(4-chlorophenyl)thiosulfonate AM8 = diisopropylthiosulfonate AM8-A and AM8-C correspond to two separate batches of AM8 synthesized. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present disclosure provides novel uses and methods, as well as compositions comprising one or more compounds selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate. The compounds are also referred to herein as "compounds of the invention." Preferably, the compounds are selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, and di-isopropylthiosulfonate. Preferably, the compounds are selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, and di-isopropylthiosulfonate.

[0008] In a preferred embodiment, the compound is bis(4-fluorophenyl) disulfide. In a preferred embodiment, the compound is bis(4-chlorophenyl) disulfide. In a preferred embodiment, the compound is bis(4-chlorophenyl) thiosulfinate. In a preferred embodiment, the compound is bis(4-fluorophenyl) thiosulfinate. In a preferred embodiment, the compound is bis(4-chlorophenyl) thiosulfonate. In a preferred embodiment, the compound is bis(4-fluorophenyl) thiosulfonate. In a preferred embodiment, the compound is di-isopropyl thiosulfonate.

[0009] It will be understood that the terms "sulphide" and "sulfide" are used interchangeably herein.

[0010] Methods for preparing the compounds referred to herein are known in the art. In some embodiments, the compounds are commercially available or can be prepared as described in Example 1.

[0011] In some embodiments, compositions are provided in which at least 50% by weight, preferably at least 90% by weight, of the active ingredient is a compound of the invention. In some embodiments, compositions are provided in which the only active ingredient is a compound of the invention, optionally including an additional antibacterial and / or anti-inflammatory agent. In some embodiments, compositions are provided in which at least 50% by weight, preferably at least 90% by weight, of the active ingredient is a compound of the invention disclosed herein. In some embodiments, compositions are provided in which the only active ingredient is a compound of the invention, optionally including an additional antibacterial and / or anti-inflammatory agent.

[0012] microbial infection The compounds disclosed herein and compositions containing them are useful for treating or preventing infectious diseases. For example, particular applications are for the treatment or prevention of respiratory infections, intestinal infections, udder infections, bovine udder infections, skin infections, bladder infections, ear infections, systemic infections, joint infections, and brain infections. Infectious diseases suitable for treatment also include, for example, bacterial prostatitis, bacterial vaginosis, biliary tract infections, chronic sinusitis, chronic lung disease, tooth decay, endocarditis, kidney stones, laryngitis, lung infections in cystic fibrosis, gingivitis, middle ear infections, nonsocial (bloodstream) infections, obstructive pulmonary disease, osteomyelitis, otitis media, periodontitis, pneumonia-prostatitis, rhinosinusitis, sinusitis, tonsillitis, tuberculosis, urinary tract infections, and wound infections.

[0013] As used herein, "infectious disease" refers to, for example, a pathogenic infection that can lead to disease. In particular, such infections are bacterial, fungal (including yeast), protozoan, or algal infections. Preferably, the infection is a microbial infection. In a preferred embodiment, the infection is a bacterial infection. In a preferred embodiment, the infection is a fungal infection (including yeast infection). In a preferred embodiment, the infection is a protozoan infection. In a preferred embodiment, the infection is an algal infection.

[0014] Treatment or prevention As used herein, "treating an infectious disease" refers to reducing the severity and / or duration of an infectious disease and / or reducing the severity and / or duration of symptoms from an infectious disease. Preferably, the treatment results in restoration of the individual's health. Preferably, the individual has fewer or shorter duration of disease symptoms. As used herein, "preventing an infectious disease" refers to preventing or alternatively delaying the onset of an infectious disease or one or more symptoms associated with an infectious disease.

[0015] The compounds disclosed herein are useful for treating acute infections.Acute infections may be characterized by microorganisms, such as bacteria, growing in a planktonic state, while chronic infections are usually associated with the presence of biofilms.In some embodiments, acute infections are characterized by infections (or symptoms of infections) lasting less than 6 months.

[0016] The compounds disclosed herein are also useful for treating chronic and / or persistent infections. The terms persistent infection and chronic infection are often used interchangeably, but they are based on different mechanisms. Persistent infections are usually suppressed by immune defenses but can become activated when such immune defenses are weakened. Persistent infections are often asymptomatic and become clinically visible only when immune defenses are unable to control the pathogen. Persistent infections are often asymptomatic, but there are well-known means for detecting such persistent infections, including, for example, detecting microorganisms from patient samples (e.g., blood or urine). In chronic infections, pathogens remain in groups of cells / tissues (e.g., joints or lung tissue). Patients always experience symptoms of the disease, but these may be milder than those in the acute phase of infection.

[0017] In some embodiments, the infection is a chronic wound infection. In some embodiments, wounds treated with the compounds of the present invention contain bacteria such as Staphylococcus aureus; Streptococci; Gram-negative bacteria such as Treponema spp., Escherichia coli, Yersinia pestis, Pseudomonas aeruginosa, or yeast / fungi such as Candida spp (albicans), Cladosporidium herbarum, Trichosporum, Rhodosporidium, and Malassezia.

[0018] In some embodiments, the infection is Acinetobacter baumanni, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Piscirikettsia salmonis, Renibacterium salmoninarum, Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus agalactiae, Escherichia coli, Clostridium perfringens, Moritella viscosa, Micrococcus luteus, Lactococcus garvieae, Candida albicans, Haemophilus influenzae, Streptococcus suis, Streptococcus suis type 2, Streptococcus uberis, Cutibacterium Agnes, Treponema spp, Yersinia pestis, Streptococcus dysgalactiae, Serratia marescens, Trueperella The infection is caused by a microorganism selected from one or more of Candida albicans, Candida pyogenes, Mannheimia haemolytica, Pasteurella multocida, Pseudomonas aeruginosa, Burkolderia cepacia, Streptococcus neumoniae, Legionella neumophila, Fusobacterium necrophorum, Corynebacterium pseudotuberculosis, Streptococcus spp., Porphyromonas gingivalis, Pseudomonas aeruginosa, Enterococcus faecalis, Neisseria gonorrhoeae, Salmonella enteritidis, and Pseudomonas aeruginosa. Preferably, the infection is caused by Candida albicans.

[0019] In preferred embodiments, the bacterial infection is caused by a bacterium selected from one or more of Acinetobacter baumannii, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Piscirikettsia salmonis, Renibacterium salmoninarum, Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, Clostridium perfringens, Moritella viscosa, Micrococcus luteus, Lactococcus garvie, Candida albicans, Haemophilus influenzae, Streptococcus suis type 2, Streptococcus uberis, and Cutibacterium Agnes.

[0020] In certain embodiments, the bacterial infection is caused by a gram-negative bacterium. In certain embodiments, the bacterial infection is caused by a gram-positive bacterium. In certain embodiments, the bacterial infection is caused by a multidrug-resistant bacterium. In certain embodiments, the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA)-associated infection or a Staphylococcus epidermidis (e.g., MRSE)-associated infection.

[0021] In a preferred embodiment, the bacteria causing the infection is Escherichia coli, and preferably the bacterial infection is a recurrent urinary tract infection, a catheter-associated urinary tract infection, or a biliary tract infection.

[0022] In a preferred embodiment, the bacteria causing the infection is Pseudomonas aeruginosa, and preferably the bacterial infection is cystic fibrosis lung infection, chronic wound infection, catheter-associated urinary tract infection, chronic rhinosinusitis, chronic otitis media, bronchiectasis, chronic obstructive pulmonary disease, or contact lens-associated keratitis.

[0023] In a preferred embodiment, the bacteria causing the infection is Staphylococcus aureus, and preferably the bacterial infection is chronic osteomyelitis, chronic rhinosinusitis, endocarditis, chronic otitis media, or of an (orthopedic) implant.

[0024] In a preferred embodiment, the bacteria causing the infection is Staphylococcus epidermidis, and preferably the bacterial infection is a central venous catheter, an orthopedic implant, or chronic osteomyelitis.

[0025] In a preferred embodiment, the bacteria causing the infection is Streptococcus pneumoniae, and preferably the bacterial infection is an infection of the nasopharynx, chronic rhinitis, chronic otitis media, or an infection in chronic obstructive pulmonary disease.

[0026] In a preferred embodiment, the bacteria causing the infection is Streptococcus pyogenes, and preferably the bacterial infection is an infection of the oral cavity and nasopharynx, recurrent tonsillitis.

[0027] In some embodiments, the fungal infection is selected from the group consisting of Absidia spp., Actinomyces spp., Aspergillus spp., Botrytis spp., Candida spp., Centrospora spp., Cephalosporium spp., Ceratocystis spp., Chaetoconidium spp., Chaetomium spp., Cladosporium spp., Colletotrichum spp., Conidiobolus spp., Fulvia spp., Fusarium spp. (including Fusarium oxysporum), Geotrichum spp., Guignardia spp., Helminthosporium spp., Histoplasma spp., Lecythophora spp., Malassezia spp., Nectria spp., Nocardia spp., Oospora The fungal infection is caused by a fungus selected from Ophiobolus spp., Paecilomyces spp., Paracoccidioides brasiliensis, Penicillium spp., Phymatotrichum spp., Phytophthora spp., Pythium spp., Piedraia hortai, Rhizoctonia spp., Rhizopus spp., Rhodosporidium spp., Saccharomyces spp., Scerotium spp., Sclerotinia spp., Torulopsosis spp., and Trichophyton spp. In a preferred embodiment, the fungal infection is caused by Fusarium spp. In a preferred embodiment, the fungal infection is caused by Fusarium oxysporum.

[0028] In some embodiments, the protozoan infection is caused by a protozoan selected from the genera Plasmodium, Entamoeba, Giardia, Toxoplasma, Cryptosporidium, Trichomonas, Trypanosoma, Leishmania, Acanthamoeba, Naegleria, Balantidium, Babesia, and Cyclospora. Preferably, the protozoan infection is caused by a protozoan of the genus Plasmodium.

[0029] In some embodiments, the algal infection is caused by microalgae selected from the genera Prototheca, Helicosporidium, Chlorella, and Desmodesmus. Preferably, the algal infection is caused by algae of the genus Prototheca. More preferably, the algal infection is a bovine udder infection.

[0030] The determination of acute versus chronic infections is known to doctors. For example, according to the Mayo Clinic, four or more yeast infections within a year indicate the presence of a chronic yeast infection, and two or more bladder infections within a six-month period indicate the presence of a chronic bladder infection (also called a recurrent urinary tract infection).

[0031] The most common method for treating bacterial pathological infections is the use of antibiotics. Current antibiotics act primarily through growth-dependent mechanisms and target rapidly dividing bacteria. However, non-replicating or slow-growing bacteria (e.g., dormant persister cells) exhibit high levels of antibiotic tolerance and / or resistance, contributing to persistent and recurrent infections. The compounds disclosed herein are suitable for use in infections involving antibiotic-resistant bacteria, antibiotic-tolerant bacteria, and antibiotic-persistent bacteria. The compounds disclosed herein are also suitable as second-line therapy, or rather, for individuals who have not responded to previous treatments (e.g., antibacterial treatments) or for disorders that have recurred within, for example, one year or six months.

[0032] As shown in Example 5, the compounds disclosed herein also result in little or no resistance, which is an advantage for antibiotic treatment.

[0033] In some embodiments, microbial infections also include infections caused by microorganisms on indwelling devices (e.g., medical implants, catheters, etc.) In some embodiments, the compounds and compositions disclosed herein are useful for treating and preventing infections of implanted medical devices, such as joint prostheses and heart valves, as further disclosed herein.

[0034] In some embodiments, the compounds and compositions disclosed herein are also useful for preventing or reducing inflammation in response to infection. Inflammation is part of a complex biological response of body tissues to harmful stimuli, such as pathogens, and is a protective response involving immune cells and molecular mediators. The function of inflammation is to eliminate pathogens.

[0035] In a preferred embodiment, treatment of an individual with a compound disclosed herein or a composition comprising the same prevents or reduces clinical inflammation in an animal, e.g., a cow. Preferably, treatment prevents or reduces (clinical) inflammation of the udder of a bovine animal. In another embodiment, treatment of an individual with the compound, or a composition comprising the same, prevents or reduces (clinical) inflammation in a human. For example, treatment prevents or reduces inflammation of the skin, preferably preventing eczema.

[0036] In addition to the compounds described herein, additional anti-inflammatory agents can be administered to suppress the inflammatory response and reduce tissue damage. In preferred embodiments, the treatments (both therapeutic and prophylactic) disclosed herein further include administration of an anti-inflammatory agent. Anti-inflammatory agents include, for example, nonsteroidal anti-inflammatory agents (COX / LOX inhibitors) such as ibuprofen, paracetamol, aspirin, diclofenac, ketoprofen, tolmetin, etodolac, and fenoprofen. Natural anti-inflammatory agents such as curcumin, ginger, spirulina, cayenne, cinnamon, cloves, sage, rosemary, black pepper, natural aspirin, boswellia, sangunaria, and / or green tea may also be used. In some embodiments, the methods and uses disclosed herein include combination treatment with a therapeutic organosulfur compound disclosed herein and an anti-inflammatory agent. The compounds may be administered together or separately. In some embodiments, a composition is provided comprising a therapeutic organosulfur compound disclosed herein together with an anti-inflammatory agent.

[0037] In some embodiments, the methods preferably comprise administering a composition comprising a compound disclosed herein to an individual in need thereof to treat or prevent an infection, particularly a bacterial, fungal, yeast, protozoan, or algal infection. In some embodiments, the composition may be administered to an individual for the treatment (e.g., therapeutic) or prevention (e.g., prophylactic) of a disease or disorder or infection. In some embodiments, the individual has or is at risk of developing a microbial infection.

[0038] The composition can be administered to any individual, particularly an animal. Preferably, the animal is a ruminant (such as a cow or goat), more preferably a cow. In some embodiments, the animal is not a cow. Preferably, the animal is a non-ruminant, such as a monogastric animal, a rodent, a non-human primate, a pig, a horse, a dog, a cat, or a bird. In preferred embodiments, the animal is a human. In some embodiments, the animal is a non-human animal. In some embodiments, the animal is an aquatic animal, such as a fish, a mollusk, and a crustacean. Preferably, the animal is a mammal or a bird.

[0039] Without wishing to be bound by theory, the present disclosure provides that the compositions disclosed herein can have beneficial effects after a single administration.In a preferred embodiment, the effects are achieved by providing a single oral administration of the compositions disclosed herein.Such oral administration may be, for example, a tablet that provides sustained release of the compounds disclosed herein.

[0040] The present disclosure also provides for multiple administrations. For example, the composition can be provided once a day, daily, weekly, or monthly. In an exemplary embodiment, the composition can be provided once a day for one week, or until symptoms are alleviated. Because the compounds disclosed herein cause little or no tolerance, they can be discontinued or used for multiple treatments as needed once symptoms are alleviated.

[0041] The actual dosage levels of the pharmaceutical formulations described herein may be varied to obtain an amount of active ingredient, composition, and mode of administration that is effective to achieve the desired therapeutic response for a particular patient without being toxic to the patient. The selected dosage level will depend on a variety of factors, including the activity of the particular compound, the route of administration, the timing of administration, the excretion rate of the particular compound used, the duration of treatment, other drugs, compounds, and / or materials used in combination, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical field. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

[0042] Those skilled in the art recognize that smaller animals have higher metabolic rates and therefore require larger drug doses on a body weight basis. Dose conversion between animals and between humans and animals is reviewed in Nair and Jacob (J Basic Clin Pharm. March 2016-May 2016;7(2):27-31) and Holliday, et al., (1967 The Relation of Metabolic Rate to Body Weight and Organ Size. A Review. Pediat. Res. 1:185-195).

[0043] In some embodiments of the methods and uses disclosed herein, at least 5 mg / day of a compound disclosed herein is provided to a human (e.g., by oral administration). Preferably, at least 10 mg / day of the compound is provided. In some embodiments, the compound disclosed herein is provided to a human at a dose of 0.1 mg / kg to 100 mg / kg. Such amounts of compound are particularly useful when the compound is provided systemically (e.g., orally). One skilled in the art will recognize that smaller amounts can be used when administered topically (e.g., to the skin, gums, or wounds). The compositions disclosed herein are preferably provided for at least one week, or until symptoms are alleviated. Such compositions can be provided several times (e.g., once a week, once a month, twice a year, etc.), although prophylactic and therapeutic effects are observed after a single use.

[0044] In some embodiments, compositions are provided that include a compound disclosed herein together with one or more additional agents, such as an antibiotic (e.g., an antibacterial, antiviral, antifungal agent), an anti-inflammatory agent, an antipyretic agent, and an analgesic agent.

[0045] In some embodiments, the compounds disclosed herein are used in combination with another antibacterial agent, such as an antifungal or antibiotic. As one skilled in the art will appreciate, the combination of the antibacterial agent with a compound described herein can reduce the dosage and / or frequency of administration of the antibacterial agent.

[0046] Exemplary antibacterial agents that may be used in combination treatment include antifungal agents such as miconazole, ketoconazole, econazole, terbinafine, ciclopirox, tolnaftate, sertaconazole, sulconazole, amphotericin b, choloxylenol, clioquinol, butenafine, naftifine, nystatin, and clotrimazole. Exemplary antibiotics include penicillin, tetracycline, cephalosporin, quinolone, lincomycin, macrolide, sulfonamide, glycopeptide, aminoglycoside, and carbapenem.

[0047] The present disclosure provides compositions comprising a compound disclosed herein together with an antibacterial agent. As one skilled in the art will appreciate, the compound and the antibacterial agent may also be provided separately. In some embodiments, the compound and the antibacterial therapy overlap. In some embodiments, therapy with a compound of the present invention precedes the antibacterial therapy.

[0048] In some embodiments, the compositions disclosed herein are provided as food compositions or in foodstuffs or functional foodstuffs.

[0049] The term "food" as used herein refers to any liquid or solid substance intended for consumption to provide nutrition and energy to a subject / organism. Food includes any type of food or animal feed, as well as functional foods. The food composition can, for example, be mixed into the food or applied to the surface of the food (e.g., as a spray or in liquid form). The food can also be immersed in the food composition. In some embodiments, the food composition prevents or inhibits spoilage of the food by microorganisms. In some embodiments, the food composition inhibits the growth of microorganisms and / or kills microorganisms on the food. One skilled in the art can identify the appropriate concentration to obtain the desired growth inhibition or killing of microorganisms.

[0050] The term "functional foods" as used herein refers to those foods that are prepared not only for their nutritional characteristics but also to perform a specific function, such as improving health or reducing the risk of disease. Such functional foods may also be called dietary supplements or (animal) food additives. For this purpose, biologically active compounds such as minerals, vitamins, fatty acids, beneficial bacteria, dietary fiber, and antioxidants are added to them. Such foodstuffs may be in any form suitable for oral ingestion, for example, liquid, gel, powder, pill, tablet, or gel capsule form.

[0051] Functional foods can also include animal digests, e.g., any material resulting from chemical and / or enzymatic hydrolysis of clean, undecomposed animal tissue. Functional foods can also include dried brewer's yeast, e.g., dried inerts that are a by-product of the brewing industry. Animal digests and dried brewer's yeast have been found to improve the mouthfeel of functional foods. When present in functional foods, animal digests comprise about 10% to about 90% of the functional food, and dried brewer's yeast comprises about 1% to about 30% of the functional food.

[0052] In some embodiments, the present disclosure provides compositions comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent, and / or excipient. (See, e.g., Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro (Editor), Mack Publishing Company, April 1997.) As used herein, the term "pharmaceutically acceptable" refers to those compositions or agents, materials, or combinations of compositions, and / or dosage forms thereof, that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Furthermore, the term "pharmaceutically acceptable diluent or carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a peptide from one organ or part of the body to another.

[0053] Pharmaceutical compositions can be administered by any suitable route and mode. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. Pharmaceutical compositions can be formulated in accordance with routine procedures for administration by any route, such as parenteral, topical (including ophthalmic), oral, sublingual, transdermal, or by inhalation. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intracoronary, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrathoracic injection and infusion. Preferred routes are oral or topical administration.

[0054] The compositions may be in any suitable form, including liquid, semi-solid, and solid dosage forms. They may be in the form of tablets, capsules, powders, granules, lozenges, creams, or liquid preparations (especially for administration to the skin or eyes), such as sterile parenteral solutions or suspensions, or in the form of sprays, aerosols, or other conventional methods for inhalation. Pharmaceutical compositions of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. In certain embodiments, the compositions are topical compositions in the form of creams, gels, ointments, lotions, foams, suspensions, sprays, aerosols, or powder aerosols. The compositions are particularly useful for administration to the skin. Suitable compositions also include oral care compositions, such as toothpastes, dentifrices, tooth powders, tooth gels, subgingival gels, mouth rinses / mouthwashes, artificial saliva, denture products, mouth sprays, lozenges, oral tablets, and chewing gums.

[0055] The present disclosure also provides cleaning or disinfecting products comprising one or more compounds disclosed herein or compositions disclosed herein. In some embodiments, the product is a solution. Solutions include cleaning solutions, disinfecting solutions, and disinfecting solutions. In some embodiments, the product is an article such as a wipe, cloth, pad, or sponge.

[0056] The present invention also provides a cleaning, disinfecting, or antiseptic composition comprising a compound of the present invention. Preferably, the composition further comprises at least one surfactant. Suitable surfactants include anionic surfactants, cationic surfactants, nonionic surfactants, or amphoteric surfactants. In some embodiments, the cleaning or antiseptic composition comprises an anionic surfactant. Anionic surfactants include, for example, alkyl sulfates (e.g., sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, ammonium laureth sulfate, sodium myreth sulfate), sulfonates (e.g., perfluorooctane sulfonate, perfluorobutane sulfonate), alkyl ether phosphates, alkylaryl ether phosphates, and carboxylates (e.g., sodium stearate, perfluorooctanoate).

[0057] In some embodiments, the cleaning or disinfecting composition comprises a cationic surfactant. Suitable cationic surfactants include, for example, quaternary ammonium compounds and their salts (e.g., cetrimonium bromide, benzalkonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide, cetylpyridinium chloride).

[0058] In some embodiments, the cleaning or disinfecting composition comprises a non-ionic surfactant. Suitable non-ionic surfactants include, for example, fatty alcohol ethoxylates, alkylphenol ethoxylates, ethoxylated amines, fatty acid amides (e.g., cocamide monoethanolamine, cocamide diethanolamine), poloxamers, polyethylene glycols, fatty acid esters of glycerol (e.g., glycerol monostearate, glycerol monolaurate), alkyl polyglucosides (e.g., decyl glucoside, lauryl glucoside, octyl glucoside), sorbitan esters (e.g., sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate), and polysorbates (e.g., Tween 20, Tween 80).

[0059] Suitable amphoteric surfactants include alkylamidopropylamine oxide, alkyldimethylamine oxide, betaines (e.g., lauryl betaine, cocoamidopropyl betaine), lauryldimethylamine oxide, and myristamine oxide.

[0060] In some embodiments, the composition comprises at least 0.1% by weight of a surfactant.

[0061] The present disclosure also provides an in vitro method comprising applying a composition disclosed herein to a surface. Preferably, the method is a method of cleaning, sanitizing, or disinfecting. More preferably, the method is a method of sanitizing or disinfecting. Compositions used in the method include, for example, cleaning compositions, sanitizing compositions, and disinfecting compositions. In some embodiments, the method comprises contacting microorganisms attached to a surface with a composition disclosed herein.

[0062] Any surface can be treated with the compounds or compositions disclosed herein to coat such surfaces. Surfaces can be, for example, sprayed, dipped, wiped, or submerged in the composition. Surfaces include glass, metal, porous, and non-porous surfaces. This also applies to the exterior and interior surfaces of potentially contaminated equipment, such as those found in the food industry or medical equipment found in hospitals and medical facilities, as well as plumbing systems (such as sink drains), countertops, building materials, ducts, clean rooms, and other surfaces. Surfaces also refer to the interior or exterior of pipes, such as drains, as well as surfaces in swimming pools, tanks (e.g., for aquaculture), purification filters, toilets, sinks, and greenhouses. Surfaces also include, for example, water from drinking troughs.

[0063] In some embodiments, the surface is a surface of a medical device such as a prosthesis (hip implant, dental implant, artificial joint, voice prosthesis, penile prosthesis), mechanical heart valve, cardiac pacemaker, arteriovenous shunt, scleral buckle, catheter (e.g., central venous catheter, intravascular catheter, urinary catheter, Hickman catheter, peritoneal dialysis catheter, endotracheal catheter), tympanostomy tube, tracheostomy tube, surgical suture instrument, bone anchor, bone screw, intraocular lens, contact lens, intrauterine device, aortofemoral graft, or vascular graft. Other medical devices include those from abdominal drains, biliary stents, breast implants, cardiac pacemakers, cerebrospinal fluid shunts, contact lenses, defibrillators, dentures, electrodialysis machines, endotracheal tubes, indwelling urinary catheters, intrauterine devices, intravenous catheters, artificial joints, mechanical heart valves, nephrostomy tubes, orthopedic implants, peritoneal dialysis catheters, artificial heart valves, artificial joint dysplasia orthopedic devices, tissue fillers, urethral stents, vascular grafts, ventricular associated pneumonia, ventricular assist devices, ventricular lead, ventricular shunts, and voice prostheses.

[0064] In some embodiments, the surface is the surface of a surgical device such as a clamp, forceps, scissors, skin hooks, tubing, needle, retractor, scaler, drill, chisel, rasp, or saw.

[0065] The present disclosure also provides an article having a surface at least partially coated with a compound of the present invention or a composition disclosed herein. In some embodiments, the article is a medical or surgical device.

[0066] In some embodiments, the in vitro method is a method of cleaning the surface. As used herein, the term "cleaning" refers to the removal of visible soil (e.g., organic and inorganic materials), dirt, debris, and / or other impurities from a surface.

[0067] In some embodiments, the in vitro method is a method of disinfecting the surface. As used herein, the terms "disinfecting," "disinfecting," or "disinfecting" refer to the reduction of the number of microorganisms to a level considered safe according to public health standards or requirements. Disinfecting does not necessarily eliminate all microorganisms on the treated surface. Those skilled in the art are well aware of such standards and requirements.

[0068] In some embodiments, the in vitro method is a method of disinfecting the surface. As used herein, the terms "disinfecting," "disinfecting," or "disinfecting" refer to the destruction and / or irreversible inactivation of pathogenic and other types of microorganisms, except bacterial spores. As used herein, the terms "inactivate" or "inactivation" refer to rendering microorganisms unable to grow / replicate. In some embodiments, the method of disinfecting eliminates all pathogenic and other types of microorganisms. In some embodiments, the disinfectant is a chemical sterilant. The chemical sterilant is a disinfectant applied for an extended exposure time and may kill spores. In some embodiments, the disinfectant is a high-level disinfectant, a mid-level disinfectant, or a low-level disinfectant. High-level disinfectants kill all microorganisms except for many bacterial spores. Mid-level disinfectants can kill mycobacteria, vegetative bacteria, most viruses, and most fungi, but not necessarily bacterial spores. Low-level disinfectants can kill most vegetative bacteria, some fungi, and some viruses. As one skilled in the art will appreciate, in some embodiments, the use of a method or disinfecting composition to disinfect a surface need not destroy or inactivate all microorganisms or all types of microorganisms to have a useful effect.

[0069] Disinfection and disinfection result in a reduction in the number of a given microorganism or colony forming units (CFU). The efficiency of disinfection or disinfection is commonly described in terms of log reduction. As used herein, the term "n-log reduction" or "n-log reduction" refers to the percentage of a given microorganism that is reduced / killed / inactivated by a disinfection or disinfection method. A 1-log reduction refers to a 90% reduction (i.e., 10-fold reduction) from the original level of the target microorganism, a 2-log reduction refers to a 99% reduction (i.e., 100-fold reduction) from the original level of the target microorganism, a 3-log reduction refers to a 99.9% reduction (i.e., 1000-fold reduction) of the target microorganism, etc.

[0070] In some embodiments, disinfection provides at least a 3 log reduction, preferably at least a 5 log reduction, and more preferably at least a 6 log reduction. In preferred embodiments, disinfection provides at least a 6 log reduction.

[0071] In some embodiments, the eradication provides at least a 1 log reduction, at least a 2 log reduction, at least a 3 log reduction, at least a 5 log reduction, at least a 6 log reduction, hi preferred embodiments, the eradication provides at least a 3 log reduction.

[0072] In some embodiments, the cleaning or disinfecting composition is contacted with the treated surface for a sufficient minimum contact time, ie, at least 30 seconds, at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 25 minutes, at least 30 minutes, at least 1 hour, or at least 2 hours.

[0073] Sanitizing and disinfecting may provide residual or long-term effectiveness against microorganisms, hi some embodiments, sanitizing or disinfecting provides residual effectiveness for at least 2 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, or at least 1 month.

[0074] In some embodiments, the disinfection or sanitization provides residual efficacy for up to 2 hours, up to 6 hours, up to 12 hours, up to 24 hours, up to 48 hours, up to 72 hours, up to 1 week, up to 2 weeks, or up to 1 month.

[0075] The present disclosure also provides for the use of a compound or composition disclosed herein as a disinfectant, sanitizer, or antimicrobial in food.

[0076] In some embodiments, the use of antimicrobial agents in food prevents or inhibits spoilage and / or decomposition of food by microorganisms. In some embodiments, the use of the antimicrobial agents inhibits the growth of microorganisms on the food and / or kills the microorganisms. One skilled in the art can identify the appropriate concentration of the antimicrobial agent to achieve the desired growth inhibition or kill of microorganisms in the food.

[0077] The present disclosure further provides agricultural compositions comprising one or more compounds of the present invention and an agriculturally acceptable excipient and / or carrier. Such carriers and solvents are known to those skilled in the art and do not unacceptably damage the plant or its environment and / or are not dangerous to the user or others who may be exposed. For example, the agriculturally acceptable carrier can be a solid carrier, a gel carrier, a liquid carrier, a suspension, or an emulsion. A non-limiting example of a solvent is water.

[0078] In some embodiments, the composition comprises at least 40% by weight, preferably at least 50% by weight, of one or more compounds of the invention, hi some embodiments, the composition comprises at least 60% by weight, preferably at least 80% by weight, more preferably at least 95% by weight, of one or more compounds of the invention.

[0079] The present disclosure includes methods for preventing or treating an infection in a plant or plant part, comprising contacting the plant or plant part with a compound of the present invention or a composition disclosed herein.

[0080] The present disclosure includes the use of a compound of the present invention or a composition disclosed herein to prevent or treat an infection in a plant or plant part.

[0081] Those skilled in the art can determine whether the compounds or compositions disclosed herein prevent or treat plant infections. Different bacteria and fungi attack different plants or plant parts, causing different symptoms. For example, bacteria or fungi may cause changes in quality characteristics, such as color, shape, size, and hardness, or rot, wounds, or shrinkage of plants or plant parts, depending on the plant's genus or species. Typically, a skilled artisan, e.g., a farmer or grower, knows which plants are associated with which quality characteristics. The compounds or compositions disclosed herein have beneficial effects on plants or plant parts. Specifically, the compounds or compositions disclosed herein prevent or treat infections in plants or plant parts. In some embodiments, the compounds or compositions disclosed herein may improve one or more quality characteristics compared to infected plants.

[0082] In some embodiments, the infection on the plant or plant part is caused by a bacterium or a fungus, hi some embodiments, the infection on the plant or plant part is caused by a bacterium selected from one or more of Xanthomonas spp., Erwinia amylovora, Rhizobium spp., Clavibacter michiganensis, Agrobacterium radiobacter, Burkholderia spp., Pseudomonadota spp., Pseudomonas spp. (preferably Pseudomonas syringae), Phytoplasma spp., and Spiroplasma spp.

[0083] In some embodiments, the infection on the plant or plant part is caused by a bacterium selected from one or more of Acidovorax, Bacillus, Dickeya, Pectobacterium, Pantoea, Burkholderia, Erwinia, Ralstonia, Rhizobium, Streptomyces, Clavibacter, Xylella, Vitis vinifera, and Agrobacterium.

[0084] In some embodiments, the infection on the plant or plant part is caused by a bacterium selected from one or more of Pseudomonas syringae pathovars, Ralstonia solanacearum, Agrobacterium tumefaciens, Xanthomonas oryzae pv. Oryzae, Xanthomonas campestris pathovars, Xanthomonas axonopodis pathovars, Erwinia amylovora, Xylella fastidiosa, Dickeya dadantii, Dickeva solani, Pectobacterium carotovorum, and Pectobacterium atrosepticum.

[0085] In some embodiments, the infection on the plant or plant part is caused by a bacterium selected from one or more of Xanthomonas campestris, Erwinia amylovora, Rhizobium spp., Clavibacter michiganensis, and Agrobacterium radiobacter.

[0086] In some embodiments, the infection on the plant or plant part is caused by a fungus selected from one or more of Pythium ultimum, Fusarium oxysporum, Fusarium solani, Phytophthora cactorum, Rhizoctonia spp. (e.g., Rhizoctonia solani), Oidium spp., Uncinula spp., Erysiphe spp., Fusarium spp., Thielaviopsis spp., Verticillium spp., Magnaporthe grisea, Sclerotinia sclerotiorum, Ustilago spp., Phakospora pachyrhizi, Puccinia spp., and Armillaria spp.

[0087] In some embodiments, the infection on the plant or plant part is caused by an oomycete, such as, for example, Pythium spp. and Phytophthora spp. In some embodiments, the infection on the plant or plant part is caused by Phytomyxea spp.

[0088] The compound or composition can be applied to plants or plant parts (including cuttings, emerging seedlings, and established vegetation including roots and above-ground parts, such as leaves, stems, flowers, fruits, branches, branches, roots, etc.), plant seeds (e.g., before germination), or surrounding soil, particularly the plant rhizosphere. As used herein, the term rhizosphere refers to the region of soil adjacent to the roots of a living plant. The width of the rhizosphere is generally within 100 mm from the root surface.

[0089] In some embodiments, the compound of the invention or a composition comprising same is applied directly to the plant, to the seeds of the plant, or to the soil of the plant or seed.

[0090] As used herein, the term "plant" includes crop plants, ornamental plants, trees, grasses, annuals, perennials, or any other commonly cultivated members of the plant kingdom. As used herein, the term "crop plant" includes plant species having commercial value that are planted and cultivated for commercial use. Thus, crop plants include flowering and non-flowering plants, perennials and annuals, trees, shrubs, vegetable plants, fruit trees, turf, and ground cover plants.

[0091] In some embodiments, the plant belongs to a family selected from the group consisting of Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, Brassicaceae or Cruciferae, Orchidaceae, Asteraceae or Compositae, Fabaceae, Cucurbitaceae, Vitis, and Vaccinia.

[0092] In some embodiments, the plant belongs to a family selected from the group consisting of Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, and Crossflowers (Brassicaceae or Cruciferae).

[0093] In a preferred embodiment, the plant belongs to the family Begoniaceae. Preferably, the plant belongs to the genus Begonia.

[0094] In a preferred embodiment, the plant belongs to the nightshade family (Solanaceae). Preferably, the plant belongs to the genus Solanum. Preferably, the plant is selected from the group consisting of tomato (S. lycopersicum), potato (S. tuberosum), eggplant (S. melongena), and pepino (S. muricatum). More preferably, the plant is tomato (S. lycopersicum) or potato (S. tuberosum).

[0095] In a preferred embodiment, the plant belongs to the Amaranthaceae family. Preferably, the plant belongs to the genus Beta. Preferably, the plant is selected from the group consisting of sugar beet (B. vulgaris, Altissima group), spinach beet or chard (B. vulgari, Cicla group), Swiss chard (B. vulgaris, Flavescens group), beetroot (B. vulgaris, Conditiva group), and mangold (B. vulgaris, Crassa group). More preferably, the plant is sugar beet (B. vulgaris, Altissima group).

[0096] In a preferred embodiment, the plant belongs to the family Rosaceae. Preferably, the plant belongs to the genus Fragaria or Malus.

[0097] In a preferred embodiment, the plant belongs to the family Brassicaceae or Cruciferae. Preferably, the plant belongs to the genus Brassica.

[0098] In a preferred embodiment, the plant belongs to the family Orchidaceae. In an exemplary embodiment, the plant is an ornamental plant such as an orchid, particularly an orchid of the genus Phalaenopsis, or another flowering plant such as a Cymbidium.

[0099] In a preferred embodiment, the plant belongs to the family Asteraceae or Compositae. Preferably, the plant belongs to the genus Chrysanthemum, Asterea, or Lactuca.

[0100] In a preferred embodiment, the plant belongs to the family Fabaceae. Preferably, the plant belongs to the genus Pisum or Phaseolus.

[0101] In a preferred embodiment, the plant belongs to the Cucumis family (Cucurbitaceae). Preferably, the plant belongs to the genus Cucumis or Cucurbita. Preferably, the plant belongs to the genus Cucumis and is selected from the group consisting of cucumber (C. sativus), sugar melon, and gherkin (C. anguria). In another preferred embodiment, the plant belongs to the genus Cucurbita and is selected from the group consisting of C. pepo (especially zucchini), and pumpkin (C. argyrosperma, C. digitate, C. maxima, and C. moschata).

[0102] In a preferred embodiment, the plant belongs to the Vitis family.

[0103] In a preferred embodiment, the plant belongs to the Vaccinia family.

[0104] In a preferred embodiment, the plant is selected from the group consisting of Begonia, Tomato, Potato, Sugar beet, Strawberry, Cabbage, Apple, Orchidaceae, Chrysanthemum, Fabaceae, Cucurbitaceae, Pisum, Vitis, Vaccinia, and Lactuca.

[0105] In a preferred embodiment, the plant is selected from the group consisting of begonia, tomato, potato, sugar beet, strawberry, cabbage, and apple.

[0106] The compounds or compositions disclosed herein can be administered in a single dose or multiple doses. For example, the compositions can be provided daily, weekly, monthly, or yearly. In an exemplary embodiment, the compounds or compositions can be provided once daily for one week, or until the compounds or compositions become effective.

[0107] In some embodiments, the compositions disclosed herein are provided as spray solutions.When the compositions are sprayed on plants, the solution can be deposited on plant parts (e.g., leaves) as droplets with small surface area ratios that evaporate, which can cause the composition to remain on plant parts (e.g., leaves) as residue.This effect can be reduced by including a wetting agent in the composition.

[0108] The amount of compound or composition applied will depend on a variety of factors, including the method of administration, the timing of administration, the rate of degradation of the particular compound used, the duration of treatment, the pesticide treatment, the compounds and / or materials used in combination, age, weight, general health and previous treatments, and similar factors well known in the agricultural arts. A horticulturist, plant grower, or farmer of ordinary skill in the art can readily determine the effective amount of compound or composition required.

[0109] It is clear to those skilled in the art that lower concentrations / amounts of the compounds disclosed herein can be administered to slow-growing plants, such as cacti and succulents. It is also clear to those skilled in the art that the concentration / amount in water and application frequency depend on the plant species, subspecies, cultivars, hybrids, and mutants. It is also clear to those skilled in the art that the dose that a plant can tolerate depends on the growth stage and size of the plant. It is also clear to those skilled in the art that the concentration / amount in water and application frequency depend on, for example, light, temperature, evaporation, nutrient concentration and pH in the root substrate, air movement, and the application of other pesticides. It is also clear to those skilled in the art that the concentration / amount in water and application frequency depend on the moment it is administered, day, night, and season and weather conditions.

[0110] As used herein, the word "comprise" and its conjugations are used in their open-ended sense to mean that items following the word are included, but items not specifically mentioned are not excluded. Additionally, the verb "consisting of" can be substituted with "consisting essentially of," which means that a compound or ancillary compound defined herein may contain additional components beyond those specifically identified, and that such additional components do not alter the unique characteristics of the invention.

[0111] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0112] The word "approximately" or "about" when used in connection with a numerical value (approximately 10, about 10), preferably means that the value may be 1% more or less than the given value 10.

[0113] The compounds and compositions disclosed herein are useful as therapies and in therapeutic treatments, and thus may be useful as pharmaceuticals and used in methods of preparing pharmaceuticals. In some embodiments, the present disclosure provides methods that are not treatments of the human or animal body and / or do not involve processes for altering the genetic identity of a human germline,

[0114] Here, the cells are not of a human germline sequence.

[0115] All patents and literature references cited herein are incorporated by reference in their entirety.

[0116] The present invention is further illustrated in the following examples, which do not limit the scope of the invention but merely serve to clarify it. [Example]

[0117] Example 1: 50 g scale synthesis of bis(p-chlorophenyl)thiosulfonate, bis(p-fluorophenyl)thiosulfonate, and bis(iso-propyl)thiosulfonate. Scope. This example describes the synthesis of bis(p-chlorophenyl)thiosulfonate (Compound 1a), bis(p-fluorophenyl)thiosulfonate (Compound 1b), and bis(iso-propyl)thiosulfonate (Compound 2).

[0118] Experimental Design: Synthesis of compounds began with 10 g pilot runs to evaluate reactions. Based on yields obtained and observations, further scale-up was performed or more detailed investigations were undertaken.

[0119] Synthesis of bis(p-chlorophenyl)thiosulfonate (compound 1a) The first attempt was carried out following the suggestions on a 10 g scale using oxidation conditions found in the literature (ACS Catal. (2020), 10, pp. 8765-8779). Scheme 1. Synthesis of compound 1a: [ka]

[0120] In the first test reaction, the mixture was kept at room temperature for 48 hours to give compound 1a as a mixture containing starting material, as well as compounds 3a and 7. Scheme 2. Product formation during the reaction [ka]

[0121] Crude compound 1a was analyzed by LCMS-24 at UV 265 nm. For analysis, an Agilent 1290 Infinity II series with a UV detector, an ELSD 1290 Infinity II detector, and an Agilent 6135 mass detector were used, equipped with a Waters XSelect CSH C18 2.5 μm 2.1 × 50 mm (PN: 186006101) column. Mobile phase A was 10 mM ammonium bicarbonate, pH 9.5 (aqueous), and mobile phase B was acetonitrile. UV detection was performed at 265 nm. The main peak eluted at Rt = 3.86 min. Mass analysis of the main peak (Rt = 3.86 min) indicated a mixture of compound 1a [M+18] and compound 3a.

[0122] The crude product was washed with warm water to remove 4-chlorobenzenesulfonic acid, which also removed other minor impurities, leaving the starting material in the mixture. The cake was then washed with pentane, which removed the starting material and gave the pure compound.

[0123] After the first 10 g test, a second batch was run on a 50 g scale. After purification, the quantities of both batches did not meet the requirements.

[0124] A second synthesis was then performed with 50 g of substrate. The batches were combined and compound 1a (50 g) was shipped with a purity of 98%. The purity was determined by LCMS-5CL.M (sequence method) (Waters Acquity HSS T3 (2.1 × 75 mm; 1.8 μm; RRHD 1200 bar, mobile phase A: 10 mM NHOAc (water / methanol / acetonitrile 900 / 60 / 40); mobile phase B: 10 mM NHOAc (water / methanol / acetonitrile 100 / 540 / 360).

[0125] Synthesis of bis(p-fluorophenyl)thiosulfonate (compound 1b) Bis(p-fluorophenyl)thiosulfonate was synthesized by oxidation of 4-fluorobenzenethiol using N-chlorosuccinimide as described in the scheme below. [ka]

[0126] Under ambient conditions at room temperature, 10 mmol (1.28 g) of p-fluorothiophenol (compound [I]) and 15 mmol (4 g) of N-chlorosuccinimide (compound [II]) were placed in a round-bottom flask, approximately 20 mL of acetonitrile was added, and the mixture was stirred and allowed to react at room temperature. After 30 minutes, the reaction was complete. Immediately after the reaction, the mixture contained (4-fluorophenyl)thiosulfonate (compound 1b or [III] in the scheme), bis(4-fluorophenyl)thiosulfinate (compound [II]), and bis(4-fluorophenyl)disulfide (compound [V]). The reaction solution was then transferred to a 250 mL separatory funnel and extracted with ethyl acetate (30 mL x 3). The upper organic phases were combined, dried, filtered, and distilled to obtain the crude product. The crude product was transferred to a round-bottom flask, slightly heated, and ethyl acetate was added until the crude product was completely dissolved. After cooling sufficiently to separate the solid, the product was filtered to obtain the product bis(p-fluorophenyl)thiosulfonate in a yield of 70% (1.00 g). The product was a white solid with a melting point of 69-70°C.

[0127] The product was identified by NMR and fulfilled the NMR characteristics of bis(p-fluorophenyl)thiosulfonate: 1H NMR (400 MHz, chloroform-d) δ 7.58-7.55 (m, 2H), 7.36-7.32 (m, 2H), 7.12-7.08 (m, 2H), 7.06-7.02 (m, 2H).

[0128] The molecular weight was also consistent with this compound (determined by GC-MS): M = 286 daltons.

[0129] Synthesis of bis(isopropyl)thiosulfonate (compound 2) [ka] The synthesis of compound 2 was initiated on a 95 g (disulfide 1) scale. Initially, 2.1 molar equivalents (129 grams) of hydrogen peroxide were added below 45° C., but the reaction resulted in a mixture of 2 and the 2-sulfoxide, as well as potentially some 2-sulfone (or other by-products). After 24 hours, the reaction was still incomplete, and therefore was prompted by the addition of more hydroxide peroxide (0.5 + 1.0 equivalents), and a slight exothermic reaction was observed.

[0130] The reaction was followed by NMR (400 MHz, chloroform-d).

[0131] After 48 h at room temperature, the reaction was stopped and concentrated in vacuo. The crude material (190.9 g), containing some AcOH and other impurities, was applied directly to silica gel (600 g) and eluted with a gradient of 0% EtOAc to 20% EtOAc in heptane to afford 37 g of the desired compound 2 (bis(4-isopropyl)thiosulfonate) (33% yield).

[0132] The reaction was repeated on a 50 g scale to obtain the desired amount with a purity of 96.3%. The purity was determined by HPLC-MS. The molecular weight was also consistent with this compound (including NH4 present in the eluate): M = 200 Daltons.

[0133] Example 2: MIC values ​​of some (potentially pathogenic) animal-associated microorganisms Example 2a: MIC, MBEC and MBIC Assays The MIC assay in this example measures growth inhibition of planktonic microorganisms. As shown herein, several compounds tested demonstrate efficacy against planktonic bacteria. [Table 1]

[0134] 1.1 Compound Dissolution and Dilution Twenty milligrams of the compound shown in Table 3 was weighed into an Eppendorf tube. The exact weight was recorded, and the volume of solvent required to achieve an 80 mM dilution was calculated. Half of the volume was first added, followed by Tween 80, and the mixture was allowed to stand for 5 minutes. In a second step, the remaining half of the volume, DMSO, was added and resuspended to aid the dilution process. The closed tube was inverted 5-10 times and then thoroughly vortexed for at least 30 seconds. If crystals were still visible after this procedure, the tube was placed on a shaker at 37°C and 150 rpm for at least 30 minutes (indicated if the dissolution period exceeded 2 hours). The dissolved, clear dilution solution had a concentration of 80 mM and was diluted 10 times with cation-adjusted Mueller Hinton Broth 2 (MHB-II) for the MIC assay (Method 1.2) to reach a working concentration of 8 mM (0.5 mL per strain). In the case of bis(4-chlorophenyl)thiosulfonate, a low-concentration stock solution of 2 mM was prepared. To do this, the required amount of compound was weighed and the final volume of the stock solution of 2% v / v Tween 80 and 2% v / v DMSO was added to the substance. This mixture was heated in a water bath set at 40 °C with occasional shaking. When the entire amount of substance was dissolved, the volume was filled up to the final volume with growth medium. This 2 mM bis(4-chlorophenyl)thiosulfonate stock solution was used for MIC plates and diluted two-fold to obtain a test range of bis(4-chlorophenyl)thiosulfonate from 1 mM to 0.002 mM.

[0135] For the MBEC assay (Method 1.3), the solution should be diluted to a final concentration of 2 mM in 0.9% saline, then further diluted to 1 mM, 0.5 mM, 0.25 mM, and 0.125 mM in saline. These dilutions were added as treatments to 96-well plates with grown biofilms (see Method 3) (0.5 mL per strain is required). The dilutions should remain transparent. [Table 2]

[0136] 1.2 MIC assay The microorganisms shown in Table 4 were used to inoculate tryptic soy agar (TSA) plates and incubated overnight at 37°C. After incubation, 3-5 well-isolated colonies with the same morphology were selected from the TSA plates, resuspended in 2 mL of 0.9% saline with 3-6 glass beads, and vortexed. The OD at 600 nm (OD) of the bacterial suspension was measured. 600 The optical density at 10 6 OD of 0.0008, which is similar to CFU / mL 600 was diluted to

[0137] MIC assays were performed in flat-bottom 96-well microtiter plates. 50 μL of MHB-II was added to columns 2–11, and 100 μL was added to column 12 for a sterility control. 100 μL of 8 mM test compound solution (Method 1) was added to column 1. A two-fold dilution series of the solution in MHB-II was achieved by resuspending 50 μL of the 8 mM solution from column 1 to column 2. This step was repeated through column 10. The concentrations of Tween 80 and DMSO in column 1 were 2.5%, which were diluted two-fold across the plate. 50 μL of the bacterial suspension was added to columns 1–11. The microtiter plate was sealed with adhesive polyethylene film for sealing microplates (Diversified Biotech) and incubated at 37°C for 24 hours. After incubation, the OD was measured at 600 nm using a Varioskan (Thermo Fisher Scientific). The minimum concentrations that reduced the final OD of the bacterial culture by 50% (MIC) and 90% (MIC) were calculated after normalizing the resulting OD values ​​to the growth control in column 11. The assay was repeated three times in three independent experiments.

[0138] 1.3 MBEC assay Frozen aliquots of Staphylococcus epidermis ATCC 35984 and Pseudomonas aeruginosa ATCC 27853 were used to inoculate 20 mL of tryptic soy broth (TSB) in 100 mL Erlenmeyer flasks at 37°C and 150 rpm and incubated overnight (Informs). The OD of the overnight cultures was 600 was measured using a spectrophotometer (Evolotion™ 201 / 220 UV-visible spectrophotometer, Thermo Fisher Scientific) and 8 OD of 0.2 is similar to CFU / mL 600 Columns 1 to 11 were diluted to OD 600A cell suspension at 0.2% saturation was seeded into a U-shaped 96-well plate by pipetting 100 μL per well, with column 12 filled with 100 μL of medium as a sterility control. The 96-well plate was sealed with adhesive polyethylene film for sealing microplates and incubated at 37°C for 48 hours under static conditions. After the biofilm growth phase, 100 μL of treatment solution (Method 1) was added to the vial, resulting in treatment concentrations of 1 mM, 0.5 mM, 0.25 mM, and 0.125 mM, with Tween 80 and DMSO concentrations of 0.63%, 0.32%, 0.16%, and 0.08%, respectively. The same concentration was applied to four different wells of the same bacterial strain, resulting in four replicates for each concentration and strain. The treatments were incubated at 37°C for 20 hours under static conditions. After treatment, the supernatant was carefully removed, and the wells containing the biofilms were carefully washed once with 200 μL of 0.9% saline. 200 μL of saline was added to completely resuspend the biofilms. After complete homogenization, 20 μL was used for the first dilution in 180 μL of 0.9% saline prepared in a second plate. This dilution was continued up to the 10E-5 dilution step, and 100 μL of the 10E-4 and 10E-5 dilutions were plated onto TSA plates. The TSA plates were incubated at 37°C for 24 hours. The colonies on the plates were enumerated, and the colony-forming units per mL of dispensed biofilm and their average were calculated, as well as the log reduction compared to untreated samples from the same well plate. The reduction in colony-forming units is closely related to the thickness of the biofilm and, therefore, the number of bacteria present in the biofilm. Therefore, a significant reduction in colony-forming units in the biofilm was defined as a log reduction of 1 or greater. This assay was repeated twice in two independent experiments).

[0139] 1.4 MBIC assay Frozen aliquots of Staphylococcus epidermis ATCC 35984 and Pseudomonas aeruginosa ATCC 27853 were used to inoculate tryptic soy agar (TSA) plates and incubated overnight at 37°C. After incubation, 3–5 well-separated colonies with identical morphology were selected from the TSA plates, resuspended in 2 mL of 0.9% saline with 3–6 glass beads, and vortexed. The optical density of the bacterial suspension was measured using a spectrophotometer (Evolution™ 201 / 220 UV-Visible Spectrophotometer, Thermo Fisher Scientific). 600 Measured at 600 nm (OD600) and found to be 0.2 600The MBIC assay was performed in a 96-well microtiter plate. 50 μL of TSB was added to columns 2–11, and 100 μL was added to column 12 for a sterility control. 100 μL of an 8 mM test compound solution (Method 1) was added to column 1. A two-fold dilution series of the solution in TSB was achieved by resuspending 50 μL of the 8 mM solution from column 1 to column 2. This step was repeated up to column 10. The concentrations of Tween 80 and DMSO in column 1 were 2.5%, which were diluted two-fold across the plate. 50 μL of the bacterial suspension was added to columns 1–11. The microtiter plate was sealed with adhesive polyethylene film for sealing microplates (Diversified Biotech) and incubated at 37°C for 48 hours. After incubation, the supernatant was carefully removed, and the wells containing the biofilms were washed once with 100 μL of 0.9% saline. Biofilms were fixed by adding 100 μL of 0.1 M HCl and incubating at room temperature for 1 hour. After incubation, the HCl was removed, and 100 μL of crystal violet (0.1% v / v in water) was added and incubated at room temperature for 30 minutes. Unbound crystal violet was removed, and the wells were washed once with 100 μL of demineralized water. 100 μL of 30% acetic acid was added and incubated at 37°C and 150 rpm for 1 hour. The solution was resuspended and transferred to a flat-bottom 96-well plate, and the absorbance was measured at 540 nm using a spectrophotometer. This assay was repeated twice in two independent experiments.

[0140] Results and Discussion The results of the tests are presented in Tables 5 and 6. In Tables 5 and 6, several organosulfur compounds exhibit low MIC values ​​and are useful as antibacterial compounds. [Table 3] [Table 4]

[0141] Example 2b: MIC50, MIC90 and MBIC against animal and human pathogens From Example 2a, several compounds were selected for further antibacterial studies. Their selection was based on their antibacterial efficacy and stability after synthesis. The selected compounds were bis(4-chlorophenyl)disulfide, bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, and diisopropylthiosulfonate, and were tested against a variety of suspected human, animal, and plant pathogens, bacteria, and fungi.

[0142] In this study, the microbial growth inhibitory activity of organosulfur compounds was measured. Some of these compounds are commercially available (bis(4-chlorophenyl) disulfide and bis(4-fluorophenyl) disulfide). Other compounds were synthesized on demand (Table 7, Organic Synthesis). The measured microbial growth inhibition (MIC) and bactericidal (MBC) potencies were compared to those measured for the biofilm eradication compound di-n-propylthiosulfonate.

[0143] Study Design. In this study, the microbial growth inhibitory activity of several organically synthesized organosulfur compounds (Table 7, Organic Synthesis) and commercially available organosulfur compounds was measured.

[0144] Because the compounds have low solubility in water, we first evaluated the concentration at which the compounds could be dissolved using a solvent suitable for biological assays. Subsequently, stock solutions of the compounds were used in triplicate in minimum inhibitory concentration (MIC) assays at a two-fold dilution range using various bacteria from Gram-positive and Gram-negative groups, as well as the yeast Candida albicans. The concentration showing less than 10% growth after 24 hours was considered the MIC90 value, while the concentration showing 50% growth after 24 hours compared to the bacterial growth control was considered the MIC50 value. Escherichia coli and Staphylococcus aureus were used as representative Gram-negative and Gram-positive bacteria, respectively. Additionally, the yeast C. albicans was also tested. After MIC assays using diisopropylthiosulfonate and di-n-propylthiosulfonate, the minimum bactericidal concentrations were determined to determine whether growth inhibition (bacteriostatic effect) also meant cell killing (bactericidal effect). [Table 5]

[0145] Table 8 presents the strains and their origins. [Table 6]

[0146] Emulsions of test compounds were prepared as shown in Table 9. 10–20 mg of test compound was weighed into an Eppendorf tube. The required amount of Tween 80 was then added, followed by the amount of DMSO. After vigorous shaking, the resulting clear solution was diluted 10 times in Mueller Hinton Broth (MHB) for the MIC assay. For C. albicans, Sabourad broth was used, and for M. viscosa, TSB, 2% NaCl was used. The stock solution was used for the assay, followed by two-fold serial dilutions. [Table 7]

[0147] The minimum inhibitory concentration (MBIC) assay was performed as follows. A frozen aliquot of the cells of interest was used to inoculate a tryptic soy agar (TSA) plate and incubated overnight at 37°C. For C. albicans, Sabourad agar was used. M. viscosa was inoculated into liquid TSB supplemented with 2% NaCl and incubated at 15°C under static conditions for 2 days. After incubation, 3–5 well-separated colonies with the same morphology were selected from the plate, resuspended in 2 mL of 0.9% saline with 3–6 glass beads, and vortexed. For M. viscosa, the preculture was diluted 10 times with sterile demi-water. The optical density at 600 nm (OD600) of the bacterial suspension was measured, and 10 6The cells were diluted to an OD600 of 0.0008, which is similar to CFU / mL. MIC assays were performed in flat-bottom 96-well microtiter plates. Fifty μL of the appropriate growth medium—Sabourad broth for C. albicans, TSB 2% NaCl for M. viscosa, and MHB for the remaining strains—was added to columns 2–11, with 100 μL added to column 12 for a sterility control. One hundred μL of an 8 mM test compound solution (Method 1) was added to column 1. A two-fold dilution series of the solution in growth medium was achieved by resuspending 50 μL of the stock solution from column 1 to column 2. This step was repeated through column 10. The respective concentrations of Tween 80 and DMSO in column 1 were half the concentrations in the stock solutions and further diluted two-fold across the plate. Fifty μL of the cell suspension was added to columns 1–11. The microtiter plate was sealed with adhesive polyethylene film for sealing microplates (Diversified Biotech) and incubated at 37°C for 24 hours. After incubation, the OD at 600 nm was measured using a Varioskan (Thermo Fisher Scientific). The OD values ​​obtained in column 11 were normalized to the growth control, and the minimum concentrations that reduced the final OD of the culture by 50% (MIC50) and 90% (MIC90) were calculated. This assay was repeated three times in three independent experiments. The MIC90 and MIC50 values ​​were averaged, and the standard deviation was calculated. To compare the antibacterial activity of the compounds against different strains, the mean and standard deviation for each strain and compound were calculated in a bar graph (Figure 1).

[0148] The values ​​of the technical replicates in the plate (four per experiment) were plotted in GraphPad across the concentrations used to provide information on the scatter of the replicates (results not shown here).

[0149] Conclusions and Discussion The results of the MIC assay (Figure 1) show that most of the tested compounds have growth inhibitory effects against the strains in this study.

[0150] Bis(4-chlorophenyl)disulfide exhibited low solubility. Addition of solvents such as Tween 80 and DMSO allowed for a 2 mM stock solution in medium. This allowed for a maximum test concentration of 1 mM. Similarly, for bis(4-chlorophenyl)thiosulfonate, the calculated solubility is 0.013 mM. Therefore, application of solvent allowed for a maximum test concentration of 0.575 mM. Actual growth inhibitory concentrations (MICs) exceeding these maximum assay concentrations were not detected by this assay. This was observed for bis(4-chlorophenyl)disulfide with E. coli, K. pneumoniae, S. agalactiae, L. garvieae, S. uberis, S. suis type 2, S. aureus (MRSA), and A. baumannii, as well as for bis(4-chlorophenyl)thiosulfonate with E. coli, K. pneumoniae, and A. baumannii. For di-n-propylthiosulfonate and diisopropylthiosulfonate, the solubilities are 5.6 mM and 9.5 mM, respectively, so assaying up to 4 mM is still within the theoretical solubility.

[0151] Furthermore, there was low batch-to-batch variability for diisopropylthiosulfonate, which showed MIC90 values ​​within a similar range against the same species (Figure 1, columns for batches A and C, diisopropylthiosulfonate A and C, respectively). There was a clear difference in the susceptibility of C. albicans compared to the other species tested. C. albicans is likely to have a lower MIC90 value due to its higher sensitivity. It can be concluded that all compounds show growth inhibitory effects, depending on the microorganism.

[0152] The minimum bactericidal concentrations (MBC) of two compounds, diisopropylthiosulfonate and di-n-propylthiosulfonate, were determined. The MBC is the lowest concentration of compound that did not show any colonies on agar plates inoculated from the MIC assay and incubated for 20 hours at the optimal growth temperature for the strain. This assay was performed three times independently for each strain of E. coli, S. aureus, and C. albicans. Therefore, standard deviations could also be calculated (Table 10). [Table 8]

[0153] Conclusions and Discussion: It could be observed that di-n-propylthiosulfonate had the lowest MBC values ​​against all species and therefore the highest fungicidal activity.

[0154] The MIC assay (Figure 1) provides information on growth inhibition in the presence of a compound over a 24-hour time window. If exposure to the compound ceases, (surviving) cells may resume growth. By performing an MBC assay, the bactericidal effect of a compound on a specific strain is determined. Di-n-propylthiosulfonate and diisopropylthiosulfonate exhibit bactericidal activity (MBC) against E. coli and C. albicans even at growth-inhibitory concentrations (MIC90). For S. aureus, both compounds produced higher MBC values ​​compared to the MIC90 values, thereby demonstrating bactericidal activity. This means that at the MIC90 concentration, viable cells were still present. The bactericidal effect (pathogen killing) occurs with increasing concentration.

[0155] Example 3 Eradication of Staphylococcus aureus LUH 14616 biofilms by AM-8 Apart from antimicrobial-resistant (AMR) bacteria, biofilms contribute to the reduced effectiveness of antibiotics against clinical infections (Sharma D, Misba L, Khan AU. Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 8;76, 2019). Biofilms are communities of bacteria resident within a (self-produced) matrix of extracellular polymeric substances that protect bacteria, among other things, from the action of antibiotics (Penesyan A, Paulsen IT, Kjelleberg S, Gillings MR. Three faces of biofilms: a microbial lifestyle, a nascent multicellular organism, and an incubator for diversity. NPJ Biofilms Microbiomes. 2021 7(1):80. Doi:10.1038 / s41522-021-00251-2).

[0156] Scope. The purpose of this in vitro experiment was to evaluate the efficacy of AM-8 (diisopropyl thiosulfonate) against AMR Staphylococcus aureus in clinically relevant biofilms.

[0157] Experimental design. Biofilm eradication assay. Assays for bacterial reduction in mature biofilms were evaluated as previously described (Scheper HJ, Wubbolts JM, Verhagen JAM, de Visser AW, van der Wal RJP, Visser LG, de Boer MJG, and Nibbering PH. SAAP-148 eradicates MRSA persisters within mature biofilm models simulating prosthetic joint infection. Front. Microbiol. 12:625952. Doi:10.3389 / fmicb.2021.625952.eCollection 2021), with one modification: biofilms were exposed to AM-8 daily for up to 4 consecutive days. Briefly, approximately 1 × 10 bacteria in BHI were cultured. 7 CFU of logarithmic-phase bacteria were cultured for 7 days in 96-well flat-bottom polystyrene microplates sealed with breathable seals. Mature biofilms were then washed twice with PBS and then exposed to AM-8 for 24 hours or to a dilution of this compound as a control. The biofilms were then washed and re-exposed to AM-8 / its dilution on another day, or sonicated for microbiological quantification of viable bacteria at the end of each day's exposure. Results are expressed as the number of surviving bacteria on various days of exposure. Experiments were performed in triplicate.

[0158] Results: Because mature biofilms mimic clinical infection better than immature biofilms at 24 hours (Cazander G, van de Veerdonk MC, Vandenbroucke-Grauls CM, Schreurs MW, Jukema GN. Maggot excretions inhibit biofilm formation on biomaterials. Clin Orthop Relat Res; 468(10):2789-96, 2010), and antibiotics had little effect on bacteria within these bacterial communities, we evaluated the ability of AM-8 to eradicate S. aureus LUH14616 in mature biofilms over a 7-day period. Results of a dose-ranging study revealed that the biofilm-reducing effect of a single dose of AM-8 increased over time without completely eradicating bacteria within the biofilm (results not shown). Therefore, the possibility that multiple daily exposures to AM-8 might be more effective against S. aureus LUH14616 biofilms than a single dose was investigated. The results revealed that AM-8 significantly reduced bacterial numbers in mature biofilms in a dose-dependent manner as the number of daily exposures increased (Figure 24). In summary, multiple daily applications of lower doses of AM-8 were more effective than a single exposure to higher doses of this compound.

[0159] Conclusion: AM-8 is able to eliminate all bacteria within a biofilm, something that antibiotics are nearly unable to do (see also Example 4).

[0160] Example 4: Antibiotic persistence experiment Approximately 80% of clinical infections are biofilm-associated. Biofilms are structured microbial communities embedded in a 3D extracellular matrix (Penesyan et al. (2021). Three faces of biofilms: a microbial lifestyle, a nascent multicellular organism, and an incubator for diversity. NPJ Biofilms Microbiomes 7:80). This matrix provides protection for the entire bacterial community against environmental stressors, including antibiotics and immune system effector molecules. Furthermore, bacteria within biofilms, including tolerogenic and persister bacteria, are highly heterogeneous and thrive in different local microenvironments. Persisters are bacterial cells that temporarily reside in a slowed or non-growing, reduced metabolic state. They arise stochastically as well as in response to environmental cues such as antibiotics, and are typically present at detectable levels in biofilms (Prax M, and Bertram R. (2014). Metabolic aspects of bacterial persisters. Frontiers in Cellular and Infection Microbiology (Vol. 4, Issue OCT). Frontiers Research Foundation). Previous studies have reported that this slowed or non-growing, reduced metabolic state is associated with tolerance but not resistance to antibiotics (Martinez JL, and Rojo F. (2011). Metabolic regulation of antibiotic resistance. In FEMS Microbiology Reviews 35(5), 768-789). Persisters are a likely cause of reinfection in patients (Lewis K. (2010). Persister cells. Annu Rev Microbiol. 64:57-72).Bacteria within biofilms have been reported to be up to 1,000 times more resistant to multiple antibiotics than their planktonic counterparts (Sharma D, Misba L, Khan AU (2019). Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 8:76).

[0161] Range. This experiment determines the susceptibility of surviving bacteria to the antimicrobial compound bis(4-chlorophenyl) disulfide.

[0162] Experimental design. The ability of AM-2 (bis(4-chlorophenyl) disulfide) and AM-8 to reduce bacterial numbers in mature biofilms was assessed as previously described (Scheper et al. (2021) Scheper H, Wubbolts JM, Verhagen JAM, de Visser AW, van der Wal RJP, Visser LG, de Boer MJG, and Nibbering PH. SAAP-148 eradicates MRSA persisters within mature biofilm models simulating prosthetic joint infection. Front. Microbiol. 12:625952. Doi:10.3389 / fmicb.2021.625952.eCollection 2021), with one modification: biofilms were exposed to the compounds daily for up to 4 consecutive days. Briefly, antimicrobial-resistant (AMR) Staphylococcus aureus LUH14616 was grown in tryptic soy broth (TSB, Oxoid Ltd, Basingstoke, UK) at 37°C and 200 rpm to mid-logarithmic phase, centrifuged at 3,000 rpm for 10 min, and then resuspended in brain heart infusion broth (BHI, Oxoid Ltd, Basingstoke, UK). Approximately 1 × 10 cells in BHI were then cultured. 7CFU of bacteria were cultured in 96-well flat-bottom polystyrene microplates sealed with breathable seals for 7 days. Biofilms were then washed and exposed daily for 3 days to high doses of rifampicin and ciprofloxacin (both from Sigma-Aldrich) (10x minimum inhibitory concentration, i.e., the lowest concentration that caused the absence of visible growth, or MIC). Biofilms were then washed twice with PBS to remove the antibiotics and bacterial cells in suspension and then exposed to increasing concentrations of AM-2 (in PBS supplemented with 1% DMSO and 1% Tween-80) or 10x the MIC antibiotic as a control for 24 hours. Finally, released bacteria were removed by washing, and the biofilms were sonicated to assess the number of viable bacteria within the biofilm. To account for possible slow-growing bacteria, bacterial plates were reanalyzed after 1 week. Results are expressed as the number of viable bacteria (CFU / ml).

[0163] Results. Because persisters are difficult to eliminate with antibiotics and are likely to cause re-infection (Lewis, 2020), the effects of AM-2 and AM-8 on persisters within mature AMR S. aureus biofilms exposed to antibiotics were evaluated by sonication. Results revealed that AM-2 at the highest dose was effective against persisters (Figure 25). It was concluded that AM-2 is effective against bacteria in their viable state, which makes them difficult to treat with classical antibiotics.

[0164] Example 5. Repeated treatment Current antibiotics primarily act through growth-dependent mechanisms and target rapidly dividing bacteria. However, repeated antibiotic treatment to control persistent, recurrent infections can result in the emergence of antibiotic resistance. This example demonstrates that Staphylococcus aureus LUH 14616 did not develop significant antibiotic resistance after repeated exposure to diisopropylthiosulfonate.

[0165] In this example, the potential of diisopropyl thiosulfonate (AM-8) to induce resistance in AMR Staphylococcus aureus LUH 14616 was investigated using two independently synthesized batches of material.

[0166] Experimental design. Potential resistance to AM-8 was assessed as described by Habets and Brockhurst (2012) (Therapeutic antimicrobial peptides may compromise natural immunity. Biol Lett 8:416-418). Briefly, log-phase bacteria (S. aureus LUH14616) were cultured at 2 × 10 in RPMI-mod. 6 The bacterial suspension was diluted to a concentration of 100 CFU / ml. Next, 50 μl of this bacterial suspension was mixed with 50 μl of various dilutions of AM-8 or rifampicin as a control in a V-bottom 96-well plate. The plate was then covered with a plastic seal and incubated at 37°C in a shaking incubator (200 rpm) for 24 hours. The plate was then centrifuged at 2,000 rpm for 5 minutes to determine growth inhibition. To start the resistance development test, 2 × 10 6One hundred microliters of mid-log bacterial suspension containing CFU / ml was mixed with 150 μl of RPMI-mod, and 5 μl of this diluted bacterial suspension was applied to V-bottom wells containing a dilution range of AM-8 or antibiotics (various concentrations below and above the MIC) in RPMI-mod (RPMI 1640 (Sigma-Aldrich) modified with 20 mM Hepes and L-glutamine and without sodium bicarbonate, further referred to as RPMI-mod). Growth inhibition was determined after 24 h at 37°C in a shaking incubator (200 rpm). 100 μl of bacterial suspension from the 0.5×MIC well was mixed with 150 μl of RPMI-mod, and 5 μl of the diluted bacterial suspension was used to inoculate a new 96-well plate containing a dilution series of AM-8 or rifampicin. These mixtures were then incubated as described above. If resistance emerged, the concentration range of AM-8 and / or antibiotics was adjusted accordingly. This was repeated 19 times. Results are expressed as the fold increase in MIC compared to the MIC at the start of the experiment.

[0167] Results. The ability of AM-8 to induce resistance in Staphylococcus aureus LUH14616 was evaluated for two batches (four replicates each). Results revealed little increase in the MIC of AM-8 over 19 passages (occasionally a two-fold increase was observed) (Figure 26). For rifampicin, a rapid 10-fold increase in the MIC of S. aureus LUH14616 was noted between passages 4 and 5, after which the MIC further increased to 146-fold after passage 10, reaching a more than 292-fold increase after the final passage.

[0168] Conclusion: In contrast to rifampicin, AM-8 did not increase its MIC over 19 passages, indicating that no development of resistance to AM-8 occurred.

[0169] Example 6: Cytotoxicity test in Caco-2 and HepG2 cell lines To prevent health hazards to infected individuals, the cytotoxicity of antimicrobial compounds used to control infectious diseases should be tolerated during their application. In this example, exposure of Caco-2 and HepG2 cell lines to bis(4-chlorophenyl)disulfide, bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, and diisopropylthiosulfonate is shown to have cytotoxic effects on these cell lines.

[0170] As a standard test, cytotoxicity was measured in Caco-2 and HepG2 cell lines. The cytotoxicity of the above cell lines was determined by measuring the amount of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) converted by mitochondrial dehydrogenase after exposure to various concentrations of antibacterial compounds. In living cells, dehydrogenase converts soluble MTT into water-insoluble purple formazan crystals that cannot cross the cell membrane. The higher the metabolic activity of the cells, the more purple crystals are formed and the lower the cytotoxicity of the antibacterial compound.

[0171] Experimental Design. The colon adenocarcinoma cells Caco-2 and HepG2 (human liver derived) were used in the current experiment and were obtained from ATCC. The intestinal Caco-2 cell line was cultured at 75 cm 2 The cells were cultured in 96-well culture flasks. Minimum essential medium (MEM) (catalog no. 31095029, ThermoFischer Scientific) supplemented with 10% (v / v) inactivated fetal calf serum (FCS) (Gibco), 1% (v / v) non-essential amino acids (Gibco), 1% sodium pyruvate (Gibco), and penicillin (100 U / mL) / streptomycin (100 μg / mL) was used as the medium for growing cells. The cells were kept in an incubator to provide optimal moisture and temperature (37°C in a humidified atmosphere of 95% air and 5% CO2 for 72 hours). To perform the experiments, Caco-2 cells were seeded into flat-bottom 96-well plates.

[0172] HepG2 adherent cells were isolated from human liver and showed epithelial morphology. The cell culture conditions were monitored according to standard protocols. HepG2 cell lines were cultured at 75 cm 2 The cells were cultured in a 1000-well culture flask. Dulbecco's modified Eagle's minimum essential medium (DMEM) + Glutamax supplemented with 10% (v / v) inactivated fetal calf serum (FCS) (Gibco) and penicillin (100 U / mL) / streptomycin (100 μg / mL) was used as the medium for growing cells. The cells were kept in an incubator to provide optimal moisture and temperature (37°C in a humidified atmosphere of 95% air and 5% CO2 for 72 hours).

[0173] Cells were grown in flat-bottom 96-well plates to an appropriate density for the experiment. For each cell line, cells were exposed to increasing concentrations of emulsified test compounds (eight concentrations ranging from 7.8 μM to 1 mM) in standard medium (catalog 31331028, ThermoFischer Scientific). Note that all experiments were performed in FBS- and antibiotic-free medium (catalog A3840101, ThermoFischer Scientific). The concentrations of Tween-80 and DMSO present in the assay to emulsify antimicrobial compounds ranged from 0.007% to 1%. Cells were incubated with emulsified test compounds for 24 hours, and the assay was performed according to standard protocols. At the end of the experiment, the medium (cell supernatant) was removed, and lysis buffer (0.04 M hydrochloric acid in propan-2-ol) was added to each well to solubilize the purple formazan crystals. As a final step, absorbance was recorded at 595 nm using a multiwell reader. Control experiments using the emulsifiers Tween 80 and DMSO, but without antimicrobial compounds, were performed in the same manner for both cell lines. Results of all experiments were expressed as the mean ± standard error of the mean (SEM) from three independent experiments performed in three replicates (three wells / condition). Differences between results were statistically evaluated using one-way analysis of variance with Bonferroni post-hoc test.

[0174] result. In Figures 2–3, control experiments were performed on both cell lines (Caco-2 and HepG2) to test the cytotoxic effects of the applied concentrations of emulsifiers Tween 80 and DMSO without antimicrobial (AM) compounds. Exposure of Caco-2 and HepG2 cell lines to increasing concentrations of emulsifiers demonstrated cytotoxic effects. In Figures 4–13, the effect of emulsified antimicrobial compounds on the cytotoxicity of Caco-2 and HepG2 cell lines is presented. DMSO 5% (denoted as D5%) was used as a positive control for cytotoxicity. The bottom x-axis represents the concentrations of Tween 80 and DMSO present in the assay to emulsify the antimicrobial compounds, ranging from 0.007% to 1%. The following antimicrobial compounds were tested and are designated as follows: AM2, bis(4-chlorophenyl) disulfide; AM3, bis(4-fluorophenyl) disulfide; AM6, bis(4-chlorophenyl) thiosulfonate; and AM8, diisopropyl thiosulfonate. AM8-A and AM8-C correspond to two separate batches of synthesized AM8.

[0175] Because emulsifiers also showed cytotoxic effects that were indicative of the antimicrobial cytotoxicity, the effects of emulsifiers (Figures 2-3) should be subtracted from the total cytotoxicity. AM8 (diisopropylthiosulfonate, Figures 10-13) is an exception because this antimicrobial compound requires little emulsifier. Notably, compared to the other AM compounds, no DMSO and 30-fold less Tween-80 were used to emulsify AM8.

[0176] Based on the results obtained, it was concluded that all compounds exhibited a slight cytotoxic effect, with the least cytotoxicity observed when Caco-2 and HepG2 cells were exposed to diisopropylthiosulfonate (AM8, Figures 10-13).

[0177] Example 7: Treatment of infected plant crops Example 7a In this example, the antimicrobial activity of compounds of the present invention against plants and plant parts is tested.

[0178] For this purpose, plants from the group consisting of Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, and Brassicaceae are selected. Infections caused by various bacteria and fungi are tested. In particular, the antibacterial activity of the compounds of the present invention is tested against pathogenic fungi selected from Pythium ultimum, Fusarium oxysporum, Fusarium solani, Phytophthora cactorum, and Rhizoctonia solani, as well as pathogenic bacteria selected from Xanthomonas campestris, Erwinia amylovora, Rhizobium spp., Clavibacter michiganensis, and Agrobacterium radiobacter. An exemplary summary of infected plants is shown in Table 11 below. [Table 9]

[0179] Example 7b. Inhibition of fungal and bacterial plant pathogens by antimicrobial compounds. Many crops in the groups Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, and Brassicaceae are infected by plant pathogens of the fungal genera Pythium, Fusarium, Phytophthora, and Rhyzoctonia, and the bacterial genera Xanthomonas, Erwinia, Rhizobium, Clavibacter, and Agrobacterium. In this example, the growth of fungal and bacterial plant pathogens was shown to be inhibited by the above-mentioned antimicrobial compounds, acting as effective control agents.

[0180] In this example, the antimicrobial activity of the compounds of the present invention is tested on plant pathogens. Di-n-propylthiosulfonate (QQ2) was used as a reference compound.

[0181] In particular, the antimicrobial activity of bis(p-chlorophenyl) disulfide (AM2), bis(p-fluorophenyl) disulfide (AM3), bis(p-chlorophenyl) thiosulfonate (AM6), and diisopropyl thiosulfonate (AM8) of the present invention is tested against pathogenic fungi selected from Pythium aphanidermatum, Phytophthora cinnamiomi, Fusarium oxysporum, Sclerotinia sclerotiorum, Rhizoctonia solani, and Botrytis cinerea.

[0182] Experimental design. The effect of the above compounds on fungal growth was tested on agar plates using various dilutions of the compounds. The fungus was inoculated in the center of the agar plate. At various time intervals, the diameter of the colony was measured.

[0183] The fungi are pre-grown on the indicated agar media as shown in Table 12. [Table 10]

[0184] The fungus was pre-grown on a suitable agar medium, such as potato dextrose agar or malt extract agar, at 24° C. After 3, 7, 10, and 14 days of incubation at 24° C., the diameter of the fungal colonies was measured on the agar plates. As the agar plates were 8 cm in diameter, this was the maximum colony size.

[0185] Agar plates were prepared with various dilutions of bis(p-chlorophenyl) disulfide (AM2), bis(p-fluorophenyl) disulfide (AM3), bis(p-chlorophenyl) thiosulfonate (AM6), and diisopropyl thiosulfonate (AM8).

[0186] To prevent heat-dependent degradation of the compounds, test compounds were added to the agar medium when the liquid agar medium was still at body temperature. A 50x concentrated stock solution of each dilution of the antimicrobial compound was prepared in 50% Tween-80 and 50% DMSO (thus, the concentrations of DMSO and Tween 80 were the same for all agar plates). The following concentrations of the antimicrobial compound were used for each strain in the agar plates: 1.0 mM, 0.50 mM, 0.25 mM, 0.125 mM, and 0.063 mM in the corresponding medium, as shown in Table 12. Each concentration was tested in quadruplicate in 8-cm diameter Petri dishes, each containing 11 ml of agar medium.

[0187] The plates were then inoculated in the center of the dish. Incubation was carried out at 24°C. Colony diameters were measured at t = 3, 7, 10, and 14 days after inoculation. Since the diameter of the Petri dish was 8 cm, this was the largest diameter measured.

[0188] Results. Figures 14-19 present the effects of various antimicrobial compounds after 7 days of incubation, clearly demonstrating differences in growth inhibition on the seventh day of incubation. Larger colony diameters indicated less growth inhibition. Pythium (Figure 14) did not show any significant growth at the tested concentrations of antimicrobial compounds at seven days post-inoculation (growth inhibition was observed at earlier time points), while the growth of other fungi was inhibited. Phytophthora cinnamiomi (Figure 15), Fusarium oxysporum (Figure 16), and Sclerotina sclerotiorum (Figure 17) were most sensitive to the antimicrobial compounds. Furthermore, growth inhibition depended on the antimicrobial compound applied and the fungus to which it was applied. Furthermore, growth inhibition of Phytophthora cinnamiomi and Fusarium oxysporum was concentration-dependent. In particular, higher concentrations of the antimicrobial compounds showed greater growth inhibition (Figures 15-16). The raw data from the experiments at t = 3, 7, 10, and 14 are presented in Figures 20-23. The antimicrobial agents tested are labeled as follows: Product 2, bis(4-chlorophenyl) disulfide (AM2); Product 3, bis(4-fluorophenyl) disulfide (AM3); Product 6, bis(4-chlorophenyl) thiosulfonate (AM6); Product 8, diisopropyl thiosulfonate (AM8); and Product Q, di-n-propyl thiosulfonate (QQ2).

[0189] Conclusion: This example clearly shows that the growth of plant pathogens is inhibited by bis(p-chlorophenyl)disulfide, bis(p-fluorophenyl)disulfide, bis(p-chlorophenyl)thiosulfonate, and diisopropylthiosulfonate, demonstrating their applicability for microbial pest control in crops. Table 13 provides some examples of plant and crop pests that can be treated in the event of a pest outbreak. [Table 11]

Claims

1. 1. A compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, for use in the treatment or prevention of a microbial infection, preferably a bacterial or fungal infection.

2. 1. A method of treating or preventing a microbial infection in an individual, comprising administering to the individual in need thereof a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds.

3. 1. A composition comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, wherein the composition is a pharmaceutical composition, an agricultural chemical, or a food composition.

4. 1. An article having a surface at least partially coated with a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, wherein preferably said article is a medical or surgical device.

5. (i) a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate; (ii) a surfactant.

6. 1. An in vitro method comprising applying a cleaning or disinfecting composition to a surface, said composition comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate.

7. 7. The method of claim 6, wherein the method is a method of sanitizing or disinfecting the surface.

8. Use of a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, as a disinfectant, a sanitizer, or an antimicrobial agent in food.

9. 1. A cleaning or disinfecting product comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds.

10. 1. An agricultural composition comprising a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, and an agriculturally acceptable excipient, carrier, and / or solvent.

11. 1. A method of preventing or treating an infection on a plant or plant part, comprising contacting the plant or plant part with a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, such that the infection is prevented or treated.

12. 1. Use of a compound selected from bis(4-fluorophenyl)disulfide, bis(4-chlorophenyl)disulfide, bis(4-chlorophenyl)thiosulfonate, bis(4-fluorophenyl)thiosulfonate, bis(4-chlorophenyl)thiosulfinate, bis(4-fluorophenyl)thiosulfinate, and di-isopropylthiosulfonate, or a composition comprising at least one of said compounds, for preventing or treating infections on plants or plant parts.

13. 13. The use or method of claim 11 or 12, wherein the compound or composition is applied directly to the plant, to the seeds of the plant, or to the soil of the plant or seeds.

14. 14. The use or method according to any one of claims 11 to 13, wherein the plant is selected from the group consisting of Begoniaceae, Solanaceae, Amaranthaceae, Rosaceae, and Brassicaceae, preferably the plant is selected from the group consisting of Begonia, tomato, potato, sugar beet, strawberry, cabbage, apple, Orchidaceae, Chrysanthemum, Fabaceae, Cucurbitaceae, Pisum, Vitis, Vaccinia, and Lactuca.

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