CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority from co- pending United States Provisional Patent Application Serial No. 62/666,398, filed on May 3, 2018, and United States Provisional Patent Application Serial No. 62/669,816, filed on May 10, 2018, the contents of each of which are incorporated herein by reference in their entirety.

FIELD

[0002] The present application relates to treatments for bacterial infections. For example, the application relates to the use of a gallic acid- sulfamethoxazole conjugate, such as compounds of Formula I as defined herein, for treatment of a Lactobacillales bacterial infection or a disease, disorder or condition arising from a Lactobacillales bacterial infection.

BACKGROUND

[0003] Phytochemicals are naturally occurring biologically active compounds that are derived and purified from plants. These natural compounds which include phenolic acids, flavonoids, alkaloids, terpenoids and glycosteroids have been successfully used for the treatment of various human diseases since the dawn of ancient medicine. In particular, phytochemicals have shown potent antimicrobial activity. Their development as antibiotics however has been largely abandoned in the advent of the various classes of synthetic antibiotics.

[0004] The excessive and injudicious use of antibiotics over time has resulted in the development of new multidrug resistant bacterial strains. The combination of antibiotics with different mechanisms of action has been used to combat drug resistance as it is less likely that a pathogen will develop resistance to more than one drug simultaneously. For example, some currently available drug-drug combinations exert their activity by dual synergistic target inhibition where two drug targets are inhibited concurrently by the two drugs, creating a synergistic effect. [0005] The search for new combinations of antimicrobial compounds has uncovered replacements for existing ineffective antibiotics, but microbes eventually developed resistance to them.

[0006] The use of antibiotics in combination with natural compounds from plants (phytochemicals) has been reported. These reports have suggested that phytochemicals act as both resistance modifiers and direct inhibitors that act cohesively when combined with antibiotics, thereby increasing their sensitivity to bacterial cells.

[0007] In comparison to purely synthetic antibiotics, phytochemicals as antimicrobial agents are relatively safe for use due to their natural origin. For example, there is less concern about their metabolic products being secreted into milk. Moreover, natural products and their derivatives mimic or resemble the natural biosynthetic intermediates and endogenous metabolites. Hence, they can be taken up by the cell through active transport systems and show less side-effects.

[0008] Designing of hybrid drugs offers advantages over the administration of two individual drugs. For example, it has been noted that instead of inhibition of an individual target in the disease-associated network, modulating activity of multiple targets may be required to achieve optimal therapeutic benefit against deadly pathogens. Multi-target therapeutics can be developed by two distinct approaches, a combination of two or more different agents to inhibit dissimilar targets or designing a multi-target specific single hybrid entity.

[0009] Many specific lead generation strategies have been previously used for the rational design of inhibitors with predefined multi-target profiles, of which most frequently reported is the framework combination strategy. Presently it is widely recognized that, in contrast to“one drug, one target, one disease”, a single hybrid drug that is capable of targeting several nodes in a disease-causing network is highly beneficial for treating complex diseases because it ensures the equal uptake of its components in all the cells and enhances its pharmacokinetic properties. In this strategy, two separate bioactive pharmacophores that inhibit different targets are synthetically linked or merged into a single molecule. The major complexity that is involved in the design of these multi-action compounds lies in balancing both drug like physicochemical properties and desired multi-target profiles with unwanted off-target effects.

[0010] Jayaraman P. et ai, (Drug Design, Development and Therapy, 2013, 7:449-475) describe the in silico design of various phytochemical- antibiotic drug conjugates as multitarget inhibitors of Pseudomonas aeruginosa enzymes. A gallic acid-sulfamethoxazole compound was designed. However no compounds were actually prepared and tested.

SUMMARY

[001 1] It has been shown herein that a gallic acid-sulfamethoxazole conjugate provides surprisingly improved inhibitory activity against various Lactobacillales bacteria compared to sulfamethoxazole alone. This antibiotic inhibitory activity does not extend to other bacteria, including bacteria from the closely related family Bacillaes (e.g. Staphylococcus) and bacteria from the Escherichia , Mannheimia and Pasteurella genuses.

[0012] Accordingly, in an embodiment, the present application includes methods and uses for treating or preventing a Lactobacillales bacterial infection comprising administering an effective amount of a gallic acid- sulfamethoxazole conjugate and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof.

[0013] The present application includes methods and uses for treating or preventing a disease, disorder or condition arising from a Lactobacillales bacterial infection comprising administering an effective amount of a gallic acid-sulfamethoxazole conjugate and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof.

[0014] In some embodiments, the gallic acid-sulfamethoxazole conjugate is a compound of Formula I:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, wherein L ¹ is a linker group.

[0015] In some embodiments, the compound of Formula I is a compound of Formula la:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.

[0016] The present application also includes a compound of Formula I:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, wherein L ¹ is a linker group.

[0017] The present application also includes pharmaceutical compositions comprising a compound of Formula I, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and a pharmaceutically acceptable carrier, wherein the compound of Formula I, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, is present in an amount effective to treat a Lactobacillales bacterial infection in a subject in need thereof.

[0018] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.

DRAWINGS

[0019] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0020] Figure 1 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Enterococcus faecalis 29212 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0021] Figure 2 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Enterococcus faecium 700221 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0022] Figure 3 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Streptococcus uberis 19436 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0023] Figure 4 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Pseudomonas aeruginosa 27853 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0024] Figure 5 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Staphylococcus epidermis 12228 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0025] Figure 6 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Staphylococcus aureus 29213 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0026] Figure 7 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Escherichia coli 25422 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro-dilution assays.

[0027] Figure 8 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Mannhaemia haemolytica 29702 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0028] Figure 9 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Pasteurella multocida 43137 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0029] Figure 10 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Pseudomonas aeruginosa 1018 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays.

[0030] Figure 1 1 shows inhibitory activity of exemplary compound of Formula la (cpd) and the inhibitory activity of sulfamethoxazole (Sulf) against Streptococcus dysgalactiae 43078 bacterium at concentrations starting from 1200 pg/ml and serially diluted to 9.38 pg/ml as determined using broth micro- dilution assays

DETAILED DESCRIPTION

I. Definitions

[0031 ] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0032] In understanding the scope of the present application, the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.

[0033] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.

[0034] The term“consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0035] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies. [0036] As used in this application, the singular forms“a”,“an” and“the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including“a compound” should be understood to present certain aspects with compound or two or more additional compounds.

[0037] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A“third” component is different from the other, first, and second components, and further enumerated or“additional” components are similarly different.

[0038] The term“and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or“one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable, prodrugs, salts and/or solvates thereof means that referenced compounds exist as individual prodrugs, salts or hydrates, as well as a combination of, for example, a salt of a solvate of a compound or a solvate of a prodrug of a compound or a solvate of a prodrug salt of a compound.

[0039] The term“bacterial infection” as used herein refers to an invasion of cells or bodily tissues by a foreign undesirable bacteria. In an embodiment, the bacterial infection is a Lactobacillales infection.

[0040] The term“phytochemical” as used herein refers to a biologically active compound produced by plants. In an embodiment, the phytochemical is gallic acid.

[0041] The term “antibiotic” as used herein refers to an antimicrobial drug used in the treatment and prevention of bacterial infections. In an embodiment, the antibiotic is sulfamethoxazole.

[0042] The term “pharmaceutically acceptable salt” means an acid addition salt or a basic addition salt suitable for, or compatible with, the treatment of subjects. [0043] The term "pharmaceutically acceptable salts" embraces salts commonly used to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically acceptable acid addition salts are prepared from an inorganic acid or an organic acid. Examples of such inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Examples of appropriate organic acids include, for example, aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, malonic, galactic, and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine and procaine.

[0044] The term“solvates” as used herein refers to complexes formed between a compound and a solvent from which the compound is precipitated or in which the compound is made. Accordingly, the term“solvate” as used herein means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a“hydrate”.

[0045] The term“pharmaceutically acceptable solvate” means a solvate suitable for, or compatible with, the treatment of subjects. For pharmaceutically acceptable solvates, a suitable solvent is physiologically tolerable at the dosage used or administered.

[0046] The term “prodrug” as used herein refers to, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0047] The term“linker group” as used herein refers to any molecular structure that joins two or more other molecular structures together.

[0048] The term“alkylene” as used herein, whether it is used alone or as part of another group, means a straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix“Cni-n2”. For example, the term Ci-ioalkylene means an alkylene group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. All alkylene groups are optionally fluorosubstituted.

[0049] The term “conjugate” as used herein refers to two molecules joined together via a covalent linkage, either directly or via a linker group.

[0050] The term“compound(s) of the application” as used herein refers to a gallic acid-sulfamethoxazole conjugate and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, specifically a compound of Formula I and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.

[0051] The expression “disease, disorder or condition arising from a bacterial infection” as used herein refers to any disease, disorder or condition that is directly or indirectly caused by the presence of a bacterial infection in a subject.

[0052] The term“subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications.

[0053] When used, for example, with respect to the methods of treatment, uses, compositions and kits of the application, a subject, for example a subject“in need thereof” is a subject who has been diagnosed with, is suspected of having, may come in to contact with, and/or was previously treated for a bacterial infection or a disease, disorder or condition arising from a bacterial infection.

[0054] The term“pharmaceutical composition” as used herein refers to a composition of matter for pharmaceutical use.

[0055] The term“pharmaceutically acceptable” means compatible with the treatment of subjects.

[0056] The term“parenteral” as used herein means taken into the body or administered in a manner other than through the gastrointestinal tract.

[0057] The term“administered” as used herein means administration of an effective amount of a compound, including a compound of Formula I, or a salt and/or solvate thereof, to a cell either in cell culture or in a subject.

[0058] As used herein, the term “effective amount” or“therapeutically effective amount” means an amount effective, at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a bacterial infection, or a disease, disorder or condition arising from a bacterial infection, an effective amount of a compound is an amount that, for example, reduces the bacterial infection compared to the bacterial infection without administration of the compound. By “reducing the infection”, it is meant, for example, reducing the amount of the infectious agent in the subject and/or reducing the symptoms of the infection. Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject. The amount of a given compound or composition that will correspond to such an amount will vary depending upon various factors, such as the given compound or composition, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.

[0059] The terms“to treat”, “treating” and“treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, diminishment of extent of bacterial infection, stabilization (i.e. not worsening) of the state of the bacterial infection, preventing spread of the bacterial infection, delay or slowing of infection progression, amelioration or palliation of the bacterial infectious state, diminishment of the reoccurrence of bacterial infection, diminishment, stabilization, alleviation or amelioration of one or more diseases, disorders or conditions arising from the bacterial infection, diminishment of the reoccurrence of one or more diseases, disorders or conditions arising from the bacterial infection, and remission of the bacterial infection and/or one or more symptoms or conditions arising from the bacterial infection, whether partial or total, whether detectable or undetectable.“To treat”,“treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “To treat”, “treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with an early bacterial infection is treated to prevent progression, or alternatively a subject in remission is treated to prevent recurrence.

[0060] “Palliating” an infection, disease, disorder and/or condition means that the extent and/or undesirable clinical manifestations of an infection, disease, disorder and/or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the infection, disease, disorder and/or condition.

[0061] The term “prevention” or“prophylaxis” and the like as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a bacterial infection and/or a disease, disorder and/or condition arising from a bacterial infection or manifesting a symptom associated with a bacterial infection and/or a disease, disorder and/or condition arising from a bacterial infection.

II. Treatment methods and uses of the application

[0062] The present application includes a method of treating or preventing a Lactobacillales bacterial infection comprising administering an effective amount of a gallic acid-sulfamethoxazole conjugate and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof.

[0063] Also included in the present application is a use of gallic acid- sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to treat or prevent a Lactobacillales bacterial infection. Further, included is a use of a gallic acid-sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to prepare a medicament to treat or prevent a Lactobacillales bacterial infection. Further included is a gallic acid-sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for use to treat or prevent a Lactobacillales bacterial infection.

[0064] The present application includes a method of treating or preventing a disease, disorder or condition arising from a Lactobacillales bacterial infection comprising administering an effective amount of a gallic acid-sulfamethoxazole conjugate and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof.

[0065] Also included in the present application is a use of gallic acid- sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to treat or prevent a disease, disorder or condition arising from a Lactobacillales bacterial infection. Further, included is a use of a gallic acid-sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to prepare a medicament to treat or prevent a disease, disorder or condition arising from a Lactobacillales bacterial infection. Further included is a gallic acid-sulfamethoxazole conjugate, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for use to treat or prevent a disease, disorder or condition arising from a Lactobacillales bacterial infection.

[0066] In some embodiments, the gallic acid-sulfamethoxazole conjugate is a compound of Formula I:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, wherein L ¹ is a linker group.

[0067] In some embodiments, L ¹ comprises at least one alkylene, ester, carbonate, carbamate or amide linkage although a person skilled in the art would appreciate that other linker moieties, such as ethers, sulfones, sulfoxides, thioethers, thioamides, thioesters and/or amines can additionally, or alternatively, be present. In some embodiments, L ¹ is a Ci-Cioalkylene group. In some embodiments, L ¹ is a Ci-C6alkylene group. In some embodiments, L ¹ is a Ci-C ₄ alkylene group. In some embodiments, L ¹ is a C2-C3alkylene group.

[0068] In some embodiments, the compound of Formula I is in the form of the free acid or a pharmaceutically acceptable base addition salt of the free acid.

[0069] In some embodiments, the compound of Formula I is:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.

[0070] In some embodiments, the Lactobacillales bacteria are any of the known gram-positive bacteria classified under this order.

[0071] In some embodiments, the Lactobacillales bacterial infection is an infection of at least one bacterium belonging to the family Enterococcus. In some embodiments, the Enterococcus bacterium is an Enterococus faecium species or an Enterococus faecalis species.

[0072] In some embodiments, the Lactobacillales bacterial infection is an infection of at least one bacterium belonging to the family Streptococcus. In some embodiments, the Streptococcus bacterium is a Streptococcus uberis species or a Streptococcus dysgalactiae species.

[0073] Compounds of the application are administered to a subject, or used, in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. In an embodiment, compounds of the application are administered to the subject, or used, by oral (including sublingual and buccal) or parenteral (including, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, topical, patch, pump and transdermal) administration and the compound formulated accordingly. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. In general, compounds of the application are used in the form in which they are available and administered to subjects.

[0074] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is sterile and fluid to the extent that easy syringability exists.

[0075] In an embodiment, parenteral administration is by continuous infusion over a selected period of time. Solutions suitable for parenteral administration are prepared by known methods by a person skilled in the art. For example, the compounds of the application are prepared in water optionally mixed with a surfactant such as hydroxypropylcellulose. Dispersions are also prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0076] Compositions for nasal administration are conveniently formulated as aerosols, drops, gels or powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it contains a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. In an embodiment, the aerosol dosage forms take the form of a pump-atomizer.

[0077] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin and/or glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0078] In another embodiment, compounds of the application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they are enclosed in hard or soft shell gelatin capsules, or they are compressed into tablets, or they are incorporated directly with the food of a diet. For oral administration, the compounds of the application may be incorporated with excipients and used in the form of, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified- release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. In an embodiment, timed-release compositions are, formulated, as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In an embodiment, liposomes are formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0079] It is also possible to freeze-dry the compounds of the application and use the lyophilizate obtained, for example, for the preparation of products for injection.

[0080] In an embodiment, the compounds of the application are coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. In a further embodiment, the compounds of the application are coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates or crosslinked or amphipathic block copolymers of hydrogels.

[0081] Treatment methods comprise administering to a subject one or more compounds of the application, and optionally consists of a single administration, or alternatively comprises a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the infection, disease, disorder or condition, the age of the subject, the dosage of the one or more compounds of the application, the activity of one or more compounds of the application, or a combination thereof. [0082] In an embodiment, the one or more compounds of the application are administered or used as soon as possible after exposure to the bacteria. In an embodiment, the one or more compounds of the application are administered or used until treatment of the bacterial infection, disease disorder or condition is achieved. For example, until complete elimination of the bacteria is achieved, or until the number of bacteria has been reduced to the point where the subject’s defenses are no longer overwhelmed and can kill any remaining bacteria.

[0083] The dosage of the one or more compounds of the application, varies depending on many factors such as the pharmacodynamic properties thereof, the mode of administration, the age, health and weight of the subject, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The one or more compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.

[0084] In an embodiment, the dosage of the one or more compounds of the application is equal to or less than the dosage of the known dosage or gallic acid and/or sulfamethoxazole when used alone. Such dosages are known to or readily determined by those skilled in the art.

III. Methods of preparing compounds of Formula I

[0085] In some embodiments, the compounds of Formula I are prepared by reacting the free arylamino group of sulfamethoxazole with a bifunctional linker, followed by selective coupling of the resultant sulfamethoxazole-linker compound with an appropriately protected gallic acid, followed by deprotection. In this embodiment, a protected gallic acid is prepared by sequential esterification reactions. For example, the free carboxylic acid group is converted to a methyl ester by reacting gallic acid in methanol in the presence of an activating agent. The remaining free hydroxyl groups are then acetylated with acetic anhydride in the presence of a base. Separately, the arylamino group of sulfamethoxazole is reacted with an excess dihaloalkyl linker in the presence of a base to form the activated sulfamethoxazole-alkylhalo compound. The activated sulfamethoxazole- alkylhalo compound and protected gallic acid are then coupled in the presence of base to form the methyl ester of Formula I which is hydrolyzed to provide the compound of Formula I

[0086] A person skilled in the art would appreciate that, in an alternate method for the preparation of the compound of Formula I, the bifunctional linker may be reacted with the appropriately protected gallic acid and then coupled with sulfamethoxazole followed by deprotection to provide the compound of Formula I.

[0087] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0088] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0089] Prodrugs of the compounds of Formula I, or salts and/or solvates thereof, may be prepared, for example, by acylating available hydroxy or amino groups using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Similarly, available carboxylic acid groups may be converted to ester groups using known chemistry, for example, by activation in the presence of base and reaction with suitable groups containing a nucleophile. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters. IV. Compounds and compositions of the application

[0090] The present application also includes a compound of Formula I:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, wherein L ¹ is a linker group.

[0091] In some embodiments, L ¹ comprises at least one alkylene, ester, carbonate, carbamate or amide linkage although a person skilled in the art would appreciate that other linker moieties, such as ethers, sulfones, sulfoxides, thioethers, thioamides, thioesters and/or amines can additionally, or alternatively, be present. In some embodiments, L ¹ is a Ci-Cioalkylene group. In some embodiments, L ¹ is a Ci-C6alkylene group. In some embodiments, L ¹ is a Ci-C ₄ alkylene group. In some embodiments, L ¹ is a C2-C3alkylene group.

[0092] In some embodiments, the compound of Formula I is:

and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.

[0093] In some embodiments, the compound of Formula I is in the form of the free acid or a pharmaceutically acceptable basic addition salt of the free acid.

[0094] The present application also includes pharmaceutical compositions comprising a compound of Formula I, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and a pharmaceutically acceptable carrier, wherein the compound of Formula I, and/or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, is present in an amount effective to treat a Lactobacillales bacterial infection in a subject in need thereof.

[0095] In some embodiments, the Lactobacillales bacterial infection is an infection of at least one bacterium belonging to the family Enterococcus. In some embodiments, the Enterococcus bacterium is an Enterococus faecium species or an Enterococus faecalis species.

[0096] In some embodiments, the Lactobacillales bacterial infection is an infection of at least one bacterium belonging to the family Streptococcus. In some embodiments, the Streptococcus bacterium is a Streptococcus uberis species or a Streptococcus dysgalactiae species.

[0097] The following non-limiting examples are illustrative of the present application. As is apparent to those skilled in the art, many of the details of the examples may be changed while still practicing the methods, compositions and kits described herein.

EXAMPLES

Example 1. Preparation of the compound of Formula la

Step 1

[0098] To a suspension of 1 (5 gm, 29.41 mmol) in methanol (50 mL) was added thionyl chloride (4.19 gm, 35.29 mmol) at 0°C. The mixture was allowed to stir for 5 hr in at room temperature. After completion, the reaction mixture was evaporated to dryness under vacuum pressure. White solid 2 was used directly in Step 2.

Step 2

[0099] To a suspension of 2 (4 gm, 21.72 mmol) in dichloromethane (DCM) (30 mL) was added triethylamine (6.6 gm, 65.16 mmol) and acetic anhydride (6.5 gm, 65.16 mmol) at 0°C. The mixture was allowed to stir for 2 hr room temperature. After completion, the reaction mixture was diluted with water and extracted by dichloromethane three times. The collected organic phase was dried over anhydrous Na2S0 ₄ , concentrated and purified by column chromatography (12% EtOAc in Hexane) to obtain 3 (5 gm, 16.12 mmol, 74 % yield) as a white solid. ¹ H NMR (500 MHz, CDCb): (2H, s), 3.90 (3H, s), 2.30 (3H, s), 2.29 (3H, s).

Step 3

[00100] To a stirred solution of 4 (500 mg, 1.97 mmol) in diemethylformamide (DMF), dibromoethane 5 (741 mg, 3.94 mmol) and potassium carbonate (682 mg, 4.94 mmol) was added. The mixture was allowed to stir for 1 hr at room temperature. After completion, the mixture was extracted with ethyl acetate two times. The collected organic phase was dried over anhydrous Na2S0 ₄ , concentrated and purified by column chromatography (9 % EtOAc in Hexane) to obtain 6 (450 mg, 1.25 mmol, 63 % yield) as colorless oil.

Step 4

[00101 ] To a stirred solution of 6 (300 mg, 0.83 mmol) and 3 (284 mg, 0.91 mmol) in DMF, potassium carbonate (230 mg, 1.66 mmol) was added. The mixture was allowed to stir for 1 hr at room temperature. Then reaction mixture was heated at 70 °C for 4 hr. After completion, the mixture was extracted with ethyl acetate two times. The collected organic phase was dried over anhydrous Na2S0 ₄ , concentrated and purified by column chromatography (60 % EtOAc in Hexane) to obtain 7 (100 mg, 0.21 mmol, 26 % yield) as a colorless oil.

Step 5

[00102] To a stirred solution of 7 (90 mg, 0.19 mmol) 1 N NaOH solution was added at 0 °C. The mixture was allowed to stir for 30 min at room temperature. After completion, the mixture was extracted with ethyl acetate two times. The collected aqueous phase was neutralized with sodium hydrogen sulphate then extracted with ethyl acetate two times. The organic phase was dried over anhydrous Na2S0 ₄ , concentrated and purified by column chromatography (80 % EtOAc in Hexane) to obtain la (70 mg, 0.15 mmol, 82 % yield) as a white solid. ¹ H NMR (500 MHz, CDC ): (2H, d, J = 14.5 Hz), 6.92 (2H, s), 6.59(2H, d, J = 15.0 Hz), 6.39 (1 H, s), 6.23 (2H, s), 4.15-4.1 1 (2H, m), 4.06-3.97 (2H, s), 2.34 (3H, s). Example 2: Minimum Inhibitory Concentration (MIC) Experiments

[00103] The minimum inhibitory concentration (MIC) of a compound of Formula la and sulfamethoxazole against various strains of bacteria were determined using a standard broth microdilution assay as outlined by CLSI (Int J Biol Sci. 2010; 6(6): 556-568). The Staphylococcus epidermis (ATCC#12228), Staphylococcus aureus (ATCC#29213), Pseudomonas aeruginosa (ATCC#27853), Enterococcus faecium (ATCC#700221 ), Enterococcus faecalis (ATCC#29212), Mannhaemia haemolytica (ATCC#29702), Pasteurella multocida (ATCC#43137), Streptococcus uberis (ATCC#19436), Streptococcus dysgalactiae (ATCC#43078), Escherichia coli (ATCC#25422) and Pseudomonas aeruginosa 1018 strains were subcultured in Brain Heart Infusion Broth (BHIB) from -80°C stock, and the cultures were subsequently incubated at 37°C overnight. Bacterial suspensions were adjusted to 0.5 McFarland turbidity as per standard CLSI protocol (Approx cell density 1.5x10 ⁸ CFU/mL) by using media for dilution. The stock solution of the compound of Formula la was made by dissolving 24mg of the compound in 1 ml of 99.9% Dimethyl Sulfoxide (DMSO) which was then resuspended in 9ml of broth, to provide a 2400ug/ml stock solution. A sulfamethoxazole stock solution was made using the same procedure. 100mI of plain broth was added to each well including the positive control wells. The wells comprising the compound of Formula I and the well containing sulfamethoxazole were serially diluted from 1200 to 9.38pg/ml as required according to the experimental procedure (Int J Biol Sci. 2010; 6(6): 556-568). The diluted test pathogens (5mI) were added to all wells with the exception of the blank well. Negative controls were taken from the bacterial suspensions and plated on Columbia agar with 5% sheep blood (Oxoid MP0351 ) to confirm purity and growth. Plates were incubated at 37°C for 18-24 h and were subsequently read automatically using 96 well plate reader (BIORAD iMark Microplate Reader) at 595nm, and a double check was made by reading manually using the Sensititre Vizion System.

[00104] Significant antibacterial activity, as compared to sulfamethoxazole alone, was found only for Enterococcus faecalis , Enterococcus faecium and Streptococcus uberis whereas other strains, including Pseudomonas aeruginosa, did not show any activity up to a concentration of 1200 pg/ml of compound of Formula la.