Compositions and methods of their use

Abstract

Provided are compositions for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA). Uses of the compositions, alone or in combination with certain other agents, are also disclosed.

Description

[0001] Docket 2217701P2WO-N 1

[0002] Compositions and Methods of Their Use

[0003] Background

[0004] Bacterial resistance to antibiotics is an increasingly pervasive problem. Methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic resistant (AR) bacteria pose threats to human health in hospitals and elsewhere. S. aureus is a gram-positive cocci-shaped bacterium that commonly colonizes human epithelia. While S. aureus is not naturally pathogenic on epithelial surfaces, infections can occur in these areas and range from pimples and impetigo to pneumonia and meningitis (Yarwood JM et al., " Quorum sensing in Staphylococcus infections", J. Clin. Invest. 112:1620-1625 (2003)). Pathogenicity can develop through the infection of S. aureus in the bloodstream, and these infections are of great medical relevance due to their prevalence and virulence. Infections caused by antibiotic-resistant strains of S. aureus have reached epidemic proportions globally (Grundmann et al., " Emergence and resurgence of methicillin-resistant Staphylococcus aureus as a public-health threat", Lancet, Sep 2; 368(9538):874-85 (2006)).

[0005] Ail implanted medical devices are susceptible to colonization by staphylococci, and staphylococcal biofilm-associated infections have been associated with devices ranging from implanted catheters to prosthetic heart valves, cardiac pacemakers, contact lenses, cerebrospinal fluid shunts, joint replacements and intravascular lines (Donlan et al., " Biofilms: survival mechanisms of clinically relevant microorganisms", Clin. Microbiol. Rev. 15:167-193 (2002)). Damaged host tissue is also a risk factor for developing biofilm-associated infection. S. epidermidis and 5. aureus, which are part of the normal skin flora, are opportunistic pathogens that can cause deep-seated skin infections, for example in burn or post-operative wounds (Hammond et al., " An in vitro biofilm model to examine the effect of antibiotic ointments on biofilms produced by burn wound bacterial isolates", Burns 37:312-321 (2011)). They are also known to form biofilms on damaged heart valves, leading to the development of life-threatening infective endocarditis (Claret et al., " The flagellar sigma factor FliA regulates adhesion and invasion of Crohn disease-associated Escherichia coli via a cyclic dimeric GMP-dependent pathway", J. Biol. Chem. 282:33275-33283 (2007)).

[0006] Brief Description

[0007] There is provided, in accordance with an embodiment of the invention, a composition comprising CBG, THCA and CBDVA wherein the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is in the range of 1:3 to 3:1, and wherein the composition is substantially free of THC. In some embodiments, the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is in the range of 1.1:1 to 1:1.1. In some embodiments, the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is 1:1.

[0008] In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 50 wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 60 wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 70% wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 80 wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 90 wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG, THCA and CBDVA constitutes at least 95 wt.% of all cannabinoids in the composition. In some embodiments, the combination of CBG,Docket 2217701P2WO-N 2

[0009] THCA and CBDVA constitutes at least 99 wt.% of all cannabinoids in the composition. In some embodiments,

[0010] In some embodiments, the composition further comprises at least one antibiotic selected from the group consisting of erythromycin, gentamicin and vancomycin. In some embodiments, the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is in the range of from 3:1 to 1:3. In some embodiments, the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is in the range of from 2:1 to 1:2. In some embodiments, the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is 1:1.

[0011] In some embodiments, the weight ratio of the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 2:1. In some embodiments, the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 5:1. In some embodiments, the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 10:1. In some embodiments, the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 20:1. In some embodiments, the weight ratio of each one of erythromycin, gentamicin and vancomycin to the others of erythromycin, gentamicin and vancomycin is in the range of 1.1:1 to 1:1.1. In some embodiments, the weight ratio of each one of erythromycin, gentamicin and vancomycin to the others of erythromycin, gentamicin and vancomycin is in the range of 1:1.

[0012] In some embodiments, the composition comprises erythromycin. In some embodiments, the composition comprises gentamicin. In some embodiments, the composition comprises vancomycin. In some embodiments, the composition comprises a combination of erythromycin and gentamicin. In some embodiments, the composition comprises a combination of erythromycin and vancomycin. In some embodiments, the composition comprises a combination of gentamicin and vancomycin.

[0013] In some embodiments, the composition also comprises at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition is in the form of a tablet or caplet. In some embodiments, the composition is in the form of a powder. In some embodiments, the composition is in the form of a liquid. In some embodiments, the composition is in the form of a paste. In some embodiments, the composition is in the form of a lozenge. In some embodiments, the composition is in the form of a gelcap. In some embodiments, the composition is contained in a capsule. In some embodiments, the liquid is formulated as an oral rinse. In some embodiments, the liquid is formulated for aerosolization or nebulization for use for oral or nasal inhalation. In some embodiments, the composition is the form of a suppository.

[0014] There is also provided, in accordance with an embodiment of the invention, a method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA), comprising contacting MRSA with a composition as described herein, in an amount and for a time efficacious to control such growth. In some embodiments, the MRSA is in a biofilm. In some embodiments, the MRSA is not in a biofilm.Docket 2217701P2WO-N 3

[0015] There is also provided, in accordance with an embodiment of the invention, a method of reducing the likelihood of infection by Staphylococcus aureus (MRSA) in a patient, or of reducing the severity of an MRSA infection in a patient, comprising administering to the patient a pharmaceutical composition as described herein.

[0016] There is also provided, in accordance with an embodiment of the invention, a method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA) in a medium, comprising contacting said medium with a composition as described herein in an amount and for a time efficacious to control such growth.

[0017] There is also provided, in accordance with an embodiment of the invention, a method for inhibiting the formation of a biofilm containing methicillin-resistant Staphylococcus aureus (MRSA) on a surface, comprising contacting said surface or a fluid which contacts said surface with a composition as described herein in an amount and for a time efficacious to inhibit such growth.

[0018] There is also provided, in accordance with an embodiment of the invention, a composition as described herein for use as a control agent for controlling the growth of MRSA.

[0019] There is also provided, in accordance with an embodiment of the invention, a composition as described herein for use as a medicine for controlling MRSA growth in a patient.

[0020] Definitions:

[0021] BCP: (-)-beta-caryophyllene, CAS registry number 118-65-0

[0022] CBD: (-)-trans-Cannabidiol, CAS registry number 13956-29-1

[0023] CBDA: cannabidiolic acid, CAS registry number 1244-58-2

[0024] CBG: Cannabigerol, CAS registry number 25654-31-3

[0025] CBGA: Cannabigerolic acid, CAS registry number 25555-57-1

[0026] CBC: Cannabichromene, CAS registry number 20675-51-8

[0027] CBCA: Cannabichromenic acid, CAS registry number 185505-15-1

[0028] CBN: cannabinol, CAS registry number 521-35-7

[0029] CBNA: cannabinolic acid, CAS registry number 2808-39-1

[0030] THC: (–)-trans-Δ9-Tetrahydrocannabinol, CAS registry number 1972-08-3

[0031] THCA: Tetrahydrocannabinolic acid (with the -COOH group at either the 2- or the 4-position, viz. ortho or para to the hydroxy group), CAS registry number 23978-85-0 or 23978-84-9 THCV: Tetrahydrocannabivarin, CAS registry number 31262-37-0

[0032] THCVA: Tetrahydrocannabivarinic acid, CAS registry number 39986-26-0

[0033] CBDV: Cannabidivarin, CAS registry number 24274-48-4

[0034] CBDVA: Cannabidivarinic acid, CAS registry number 31932-13-5Docket 2217701P2WO-N 4

[0035] deTHC mix: a mixture of cannibinoids prepared as described below, which contains principally CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, THCA, CBN, CBNA, CBC, CBCA and is free of THC

[0036] CB1receptor: cannabinoid receptor type 1

[0037] CB2receptor: cannabinoid receptor type 2

[0038] Pharmaceutical Compositions

[0039] Compositions in accordance with embodiments of the invention include pharmaceutical compositions, which can be administered to a patient to reduce the likelihood of infection by MRSA, or to reduce the severity of an MRSA infection. Such pharmaceutical compositions will thus comprise, in addition to CTC and, if present, one or more antibiotics selected from erythromycin, gentamicin and vancomycin, one or more pharmaceutically acceptable carriers or excipients. The carrier(s) or excipients must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0040] Pharmaceutical formulations are discussed more extensively, inter alia, in Remington: The Science and Practice of Pharmacy, 23rdEdition, Academic Press an imprint of Elsevier, 2021, and pages 359-380, 381-393, and 633-643 therein are incorporated herein by reference.

[0041] Pharmaceutical compositions in accordance with embodiments of the invention may also be formulated as suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods involving CTC include the step of bringing into association with CTC and, if present, one or more antibiotics selected from the group consisting of erythromycin, gentamicin and vancomycin ("active ingredients") the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0042] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredients may also be presented as a bolus, electuary or paste.

[0043] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.Docket 2217701P2WO-N 5

[0044] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multidose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0045] Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

[0046] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredients in a basis such as gelatin and glycerin or sucrose and acacia.

[0047] Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.

[0048] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Liquid formulations for use as a mouthwash may also contain, for example, other anti-bacterial agents (such as cetyl pyridinium chloride, chlorhexidine, saline, menthol, thymol, clove, eucalyptus oil, cinnamon oil, methyl salicylate), humectants (such as glycerin, sorbitol, and polyethylene glycols), surfactants (such as sodium lauryl sulphate), fluoride, alcohol, coloring agents, and / or sweetening agents.

[0049] Non-Pharmaceutical Formulations

[0050] Compositions in accordance with embodiments of the invention may be formulated for application to surfaces that may be infected with or come into contact with MRSA, including biotic and abiotic surfaces such as human epithelium, endothelium, skin, teeth, and implanted medical devices. In cases in which the compositions are to be used in a human or animal body, they should be formulated so as to be compatible for such use, e.g. as pharmaceutical formulations. In situations in which the compositions will not be used in a human or animal body or introduced thereto, they may be formulated to contain ingredients that are not compatible with the body.Docket 2217701P2WO-N 6

[0051] Experimental

[0052] The efficacy of the compositions disclosed herein against growth of methicillin-resistant Staphylococcus aureus (MRSA) and biofilm formation by MRSA were demonstrated as follows.

[0053] Materials

[0054] Erythromycin, gentamicin and vancomycin were purchased from a commercial supplier. CBG, THCA and CBDVA were either purchased from commercial suppliers. The material referred to as CTC was prepared by mixing CBG, THCA and CBDVA as oily material, 3 millimoles each combined in one ml of CTC, i.e. one ml with a concentration of 3 micromolar of each of these cannabinoids.

[0055] Methods

[0056] Inhibition of bacterial growth: Dilutions of compounds in TSB (tryptic soy broth) were prepared in a polystyrene flat bottomed 96-well microplate. Wells with no compounds and with bacteria served as positive controls. Wells with no bacteria and with compounds served as blanks. An equal volume (100 µl) of the bacterial suspension at optical density (OD)600= 0.01 was added to each well. After a 24-h incubation at 37°C under aerobic conditions, growth was monitored by recording the OD at 600 nm using a Tecan plate reader Spectrophotometer. Each assay was performed in triplicate. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound(s) that resulted in at least 90% (MIC90) inhibition of the bacterial growth compared with that in the untreated controls.

[0057] Inhibition of biofilm formation: each assay was performed as described above for inhibition of bacterial growth, except that the bacterial medium, TSB, was supplemented with glucose 1%. After incubation for 24 h, spent media and free-floating bacteria were removed by aspiration and the wells were washed carefully three times with doubly distilled water (DDW), prior to quantification of biofilm by crystal violet staining. The minimum biofilm inhibition concentration (MBIC) was defined as the lowest concentration of compound(s) that resulted in at least 90% (MBICgo) inhibition of the formation of biofilms compared with that in the untreated controls.

[0058] Agents tested individually were the cannabinoids CTC (a mixture of CBG, THCA and CBDVA), and the antibiotics erythromycin, gentamicin and vancomycin. Different combinations of agents were also tested on MRSA growth and biofilm formation as described above. In the combinations, each agent was present in the same concentration by weight, either 5 micrograms / ml each or 2.5 micrograms / ml each, for a total concentration of the four components of either 20 micrograms / ml or 10 micrograms / ml, except that for CTC the amount was 3 micrograms of CBG, THCA and CBDVA.

[0059] Crystal violet test: 0.02% crystal violet was added to wells and left in each well for 45 min, which then was washed twice with DDW to remove unbound dye. After adding 200 µl of 30% acetic acid into each well, the plate was shaken for 10 min to release the dye, and the biofilm was quantified by measuring the absorbance at 595 nm using a Tecan plate reader Spectrophotometer. Each assay was performed in triplicate.Docket 2217701P2WO-N 7

[0060] Results

[0061] Table 1 shows the results expressed as percentage of inhibition of MRSA biofilm formation versus control for CTC, erythromycin, gentamicin, and vancomycin, each alone and in various combinations, as well as for a control (no treatment).

[0062] TABLE 1 - INHIBITION OF MRSA BIOFILM GROWTH

[0063] AGENTS(S) % growth vs control E 5 µg / ml + CTC 3 µM 5.66

[0064] G 5 µg / ml +CTC3 3 µM 5.42

[0065] V 5 µg / ml + CTC3 3 µM 5.43

[0066] E 2.5 µg / ml + G 2.5 µg / ml + CTC3 3 µM 6.07

[0067] E 2.5 µg / ml + V 2.5 µg / ml + CTC3 3 µM 6.06

[0068] G 2.5 µg / ml + V 2.5 µg / ml + CTC3 3 µM 5.49

[0069] E 1.67 µg / ml + G 1.67 µg / ml + V 1.67 µg / ml + CTC3 3 µM 5.92

[0070] E 5 µg / ml 20.61

[0071] G 5 µg / ml 6.78

[0072] V 5µg / ml 7.70

[0073] E 2.5 µg / ml + G 2.5 µg / ml 6.58

[0074] E 2.5 µg / ml + V 2.5 µg / ml 185.77

[0075] G 2.5 µg / ml +V 2.5µg / ml 6.30

[0076] E 1.67 µg / ml + G 1.67 µg / ml + V 1.67 µg / ml 4.62

[0077] CTC 3µM 11.96

[0078]

[0079] Control - no treatment 100

[0080] E = erythromycin, G = gentamicin, V = vancomycin, CTC = mixture of CBG, THCA and CBD A as described above.

[0081] From Table 1, it is clear that CTC alone is effective in inhibiting the growth of MRSA biofilm, as are combinations of CTC with (i) erythromycin (ii) gentamicin (iii) vancomycin (iv) erythromycin + gentamicin (v) gentamicin + vancomycin and (vi) erythromycin + vancomycin. The combinations may thus be suitable for controlling MRSA growth and associated infections, with reduced risk of adverse effects as well as lower cost as compared to use of each agent alone.

Claims

Docket 2217701P2WO-N 8CLAIMS1. A composition comprising CBG, THCA and CBDVA wherein the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is in the range of 1:3 to 3:1, and wherein the composition is substantially free of THC.

2. The composition of claim 1, wherein the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is in the range of 1.1:1 to 1:1.1.

3. The composition of claim 2, wherein the weight ratio of each one of CBG, THCA and CBDVA to the others of CBG, THCA and CBDVA is 1:1.

4. The composition of any one of claims 1 to 3 wherein the combination of CBG, THCA and CBDVA constitutes at least 50 wt.% of all cannabinoids in the composition.

5. The composition of claim 4 wherein the combination of CBG, THCA and CBDVA constitutes at least 60 wt.% of all cannabinoids in the composition.

6. The composition of claim 5 wherein the combination of CBG, THCA and CBDVA constitutes at least 70% wt.% of all cannabinoids in the composition.

7. The composition of claim 6 wherein the combination of CBG, THCA and CBDVA constitutes at least 80 wt.% of all cannabinoids in the composition.

8. The composition of claim 7 wherein the combination of CBG, THCA and CBDVA constitutes at least 90 wt.% of all cannabinoids in the composition.

9. The composition of claim 8 wherein the combination of CBG, THCA and CBDVA constitutes at least 95 wt.% of all cannabinoids in the composition.

10. The composition of claim 9 wherein the combination of CBG, THCA and CBDVA constitutes at least 99 wt.% of all cannabinoids in the composition.

11. The composition of any one of claims 1 to 10 wherein the composition further comprises at least one antibiotic selected from the group consisting of erythromycin, gentamicin and vancomycin.

12. The composition of claim 11, wherein the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is in the range of from 3:1 to 1:3.

13. The composition of claim 12, wherein the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is in the range of from 2:1 to 1:2.

14. The composition of claim 13, wherein the weight ratio of the collective amount of CBG, THCA and CBDVA in the composition to the collective amount of erythromycin, gentamicin and vancomycin in the composition is 1:1 to 1:1.

15. The composition of any one of claims 11 to 14, wherein the weight ratio of the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 2:1.

16. The composition of claim 15, wherein the weight ratio of the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 5:1.Docket 2217701P2WO-N 917. The composition of claim 16, wherein the weight ratio of the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 10:1.

18. The composition of claim 17, wherein the weight ratio of the collective amount of erythromycin, gentamicin and vancomycin in the composition to the collective amount of other antibiotics in the composition is at least 20:1.

19. The composition of any one of claims 1 to 18, wherein the weight ratio of each one of erythromycin, gentamicin and vancomycin to the others of erythromycin, gentamicin and vancomycin is in the range of 1.1:1 to 1:1.1.

20. The composition of any one of claims 1 to 18, wherein the weight ratio of each one of erythromycin, gentamicin and vancomycin to the others of erythromycin, gentamicin and vancomycin is in the range of 1:1.

21. The composition of any one of claims 1 to 18, wherein the composition comprises erythromycin.

22. The composition of any one of claims 1 to 18, wherein the composition comprises gentamicin.

23. The composition of any one of claims 1 to 18, wherein the composition comprises vancomycin.

24. The composition of any one of claims 1 to 18, wherein the composition comprises a combination of erythromycin and gentamicin.

25. The composition of any one of claims 1 to 18, wherein the composition comprises a combination of erythromycin and vancomycin.

26. The composition of any one of claims 1 to 18, wherein the composition comprises a combination of gentamicin and vancomycin.

27. The composition of any one of claims 1-26, which also comprises at least one pharmaceutically acceptable carrier or excipient.

28. The composition of claim 27 which is in the form of a tablet or caplet.

29. The composition of claim 27 which is in the form of a powder.

30. The composition of claim 27 which is in the form of a liquid.

31. The composition of claim 27 which is in the form of a paste.

32. The composition of claim 27 which is in the form of a lozenge.

33. The composition of claim 27 which is in the form of a gelcap.

34. The composition of claim 27 which is contained in a capsule.

35. The composition of claim 30, wherein the liquid is formulated as an oral rinse.

36. The composition of claim 30, wherein the liquid is formulated for aerosolization or nebulization for use for oral or nasal inhalation.

37. The composition of claim 27 which is the form of a suppository.Docket 2217701P2WO-N 1038. A method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA), comprising contacting MRSA with a composition according to any one of claims 1-26 in an amount and for a time efficacious to control such growth.

39. The method of claim 38, wherein the MRSA is in a biofilm.

40. The method of claim 38, wherein the MRSA is not in a biofilm.

41. A method for controlling the growth of methicillin-resistant Staphylococcus aureus (MRSA) in a medium, comprising contacting said medium with a composition according to any one of claims 1-26 in an amount and for a time efficacious to control such growth.

42. A method for inhibiting the formation of a biofilm containing methicillin-resistant Staphylococcus aureus (MRSA) on a surface, comprising contacting said surface or a fluid which contacts said surface with a composition according to any one of claims 1-26 in an amount and for a time efficacious to inhibit such growth.

43. A method of reducing the likelihood of infection by Staphylococcus aureus (MRSA) in a patient, or of reducing the severity of an M RSA infection in a patient, comprising administering to the patient a composition according to any one of claims 27 to 3744. A composition according to any one of claims 1 to 26 for use as a control agent for controlling the growth of MRSA.

45. A composition according to any one of claims 27 to 37 for use as a medicine for controlling MRSA growth in a patient.

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