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Title:
COMBINATION OF MUPIROCIN WITH PORPHYRIN-BASED PHOTOSENSITIZERS FOR REDUCING ANTIBIOTIC RESISTANCE EMERGENCE
Document Type and Number:
WIPO Patent Application WO/2022/180380
Kind Code:
A1
Abstract:
There is provided a use of a compound of formula (I) or formula (II) as defined herein to suppress the emergence of antibiotic resistance in bacteria exposed to another antibacterial agent (e.g. mupirocin). There is also provided a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent (e.g. mupirocin) for treating or preventing a bacterial infection, in which the use of the combination suppresses the emergence of antibiotic resistance. Such bacterial infections may be caused by Staphylococcus aureus or Streptococcus pyogenes, e.g. MRSA.

Inventors:
LOVE WILLIAM G (GB)
RHYS-WILLIAMS WILLIAM (GB)
Application Number:
PCT/GB2022/050477
Publication Date:
September 01, 2022
Filing Date:
February 22, 2022
Export Citation:
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Assignee:
DESTINY PHARMA PLC (GB)
International Classes:
A61K31/409; A61K31/351; A61K45/06; A61P31/04
Domestic Patent References:
WO2004056828A22004-07-08
WO2006000765A12006-01-05
WO2007074340A12007-07-05
WO2010046663A22010-04-29
Foreign References:
GB2415373A2005-12-28
Other References:
MAISCH T ET AL: "Photodynamic effects of novel XF porphyrin derivatives on prokaryotic and eukaryotic cells", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 49, no. 4, 1 April 2005 (2005-04-01), pages 1542 - 1552, XP002428611, ISSN: 0066-4804, DOI: 10.1128/AAC.49.4.1542-1552.2005
OOI N. ET AL: "XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY., vol. 65, no. 1, 4 November 2009 (2009-11-04), GB, pages 72 - 78, XP055918332, ISSN: 0305-7453, DOI: 10.1093/jac/dkp409
TUNGER, INT. J MICROB. AGENTS, vol. 15, 2000, pages 131 - 135
JORGENSEN ET AL., CLIN. INFECT. DIS., vol. 30, 2000, pages 799 - 808
PATEL, J.B. ET AL., CLINICAL INFECTIOUS DISEASES, vol. 49, 2009, pages 935 - 41
FARRELL D.J. ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, March 2011 (2011-03-01), pages 1177 - 1181
KWIATKOWSKI, P. ET AL., MICROBIAL DRUG RESISTANCE, vol. 25, no. 10, 2019, pages 1424 - 1429
KWIATKOWSKI, P. ET AL., ADVANCES IN DERMATOLOGY AND ALLERGOLOGY, vol. 36, no. 3, 2019, pages 308 - 314
KWIATKOWSKI, P. ET AL., MOLECULES, vol. 24, no. 17, 2019, pages 3105
"The Porphyrins", vol. Synthetic procedures, including those for the form, 1978, ACADEMIC PRESS
HURDLE JGO'NEILL AJINGHAM EFISHWICK CCHOPRA I: "Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modelling techniques", ANTIMICROB. AGENTS CHEMOTHER., vol. 48, 2004, pages 4366 - 4376
SUTHERLAND R ET AL., ANTIMICROB. AGENTS CHEMOTHER., vol. 27, no. 4, 1985, pages 495 - 498
SALGADO CD, CLIN. INFECT. DIS., vol. 36, 2003, pages 131 - 9
"Remington The Science and Practice of Pharmacy", 1995, MACK PRINTING COMPANY
MARTINDALE - THE COMPLETE DRUG REFERENCE
FARRELL DJROBBINS MRHYS-WILLIAMS WLOVE WG: "Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methiciiiin-resistant Staphylococcus aureus isolates during a 55-passage study", ANTIMICROB. AGENTS CHEMOTHER, vol. 55, 2011, pages 1177 - 1181
Attorney, Agent or Firm:
CARLING, David Andrew (GB)
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Claims:
Claims 1. Use of a first antibacterial agent which is a compound of formula (I) or formula (II), R4(R3)(R2)HN R1 O NH N O R1 N(R2)(R3)R4 I) II) where R1 is a C1 to C6 alkylene group; R2, R3 and R4 are independently C1 to C4 alkyl; and M is a metallic element or a metalloid element, to suppress the emergence of antibiotic resistance in bacteria exposed to a second antibacterial agent. 2. A method of suppressing the emergence of antibacterial resistance in bacteria exposed to a second antibacterial agent which method comprises exposing the bacteria to a first antibacterial agent which is a compound of formula (I) or formula (II) as defined in Claim 1. 3. The use according to Clam 1 or method according to Claim 2, wherein the compound of formula (I) or formula (II) is administered to a subject suffering from a bacterial infection or colonised with bacteria. 4. The use or method according to Claim 3, wherein the compound of formula (I) or formula (II) and said second antibacterial agent are administered to a subject suffering from a bacterial infection or colonised with bacteria, optionally wherein the compound of formula (I) or formula (II) and said second antibacterial agent are administered simultaneously.

5. The use or method according to Claim 3 or Claim 4, wherein the bacterial infection is caused by Staphylococcus sp. or Streptococcus sp., or the subject is colonised with Staphylococcus sp. or Streptococcus sp. 6. The use or method according to Claim 5, wherein the bacterial infection is caused by Staphylococcus aureus or Streptococcus pyogenes, or the subject is colonised with Staphylococcus aureus or Streptococcus pyogenes. 7. A combination comprising a compound of formula (I) or formula (II) as defined in Claim 1 and a second antibacterial agent for use in treating or preventing a bacterial infection, wherein the use of the combination suppresses the emergence of antibiotic resistance. 8. A method of treating or preventing a bacterial infection which method comprises administration of a combination comprising a compound of formula (I) or formula (II) as defined in Claim 1 and a second antibacterial agent to a subject suffering from said bacterial infection or at risk of suffering from said bacterial infection to suppress the emergence of antibiotic resistance. 9. The combination for use according to Claim 7, or the method according to Claim 8, wherein the combination is a kit-of-parts comprising components: (A) a pharmaceutical formulation comprising a compound of formula (I) or (II), and optionally one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising the second antibacterial agent, such as mupirocin, and optionally one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other. 10. A kit-of-parts comprising: (I) one of components (A) or (B) as defined in Claim 9; and (II) instructions to use that component in combination with the other of the two components, for use in treating or preventing a bacterial infection, wherein the use suppresses the emergence of antibiotic resistance.

11. The combination for use according to Claim 7 or Claim 9, the method according to Claim 8 or Claim 9, or the kit according to Claim 10, wherein the bacterial infection is a Staphylococcus sp. or Streptococcus sp. infection. 12. The use, method, combination for use or kit according to Claim 11, wherein the bacterial infection is a Staphylococcus aureus or Streptococcus pyogenes infection. 13. The use, method, combination for use or kit according to Claim 11 or Claim 12, wherein the bacterial infection is resistant to another antibiotic. 14. The use, method, combination for use or kit according to any one of Claims 11 to 13, wherein the bacterial infection is a methicillin-resistant Staphylococcus aureus or Streptococcus pyogenes infection. 15. The use, method, combination for use or kit according to any one of Claims 11 to 14, wherein the compound of formula (I) or formula (II) and the second antibacterial agent are administered simultaneously. 16. The use, method, combination for use or kit according to any one of Claims 1 to 15, wherein the compound of formula (I) or formula (II) is administered to a subject having an increased risk of suffering from a bacterial infection, e.g. an infection by Staphylococcus sp. or Streptococcus sp. 17. The use, method, combination for use or kit according to any one of Claims 1 to 16, wherein the patient is undergoing a surgical or cosmetic procedure involving penetration of the skin, such as a procedure requiring a catheter, suture or surgical drain. 18. The use, method, combination for use or kit according to Claim 16 or Claim 17, wherein the use or method is for the prevention of an exit site infection or peritonitis resulting from peritoneal dialysis. 19. The use, method, combination for use or kit according to Claim 16 or Claim 17, wherein the use or method involves nasal decolonisation of Staphylococcus sp. 20. The use, method, combination for use or kit according to any one of the preceding claims, wherein any increase in the minimum inhibitory concentration for the second antibacterial agent is reduced compared to the increase in the minimum inhibitory concentration for the second antibacterial agent that would occur in the absence of the compound of formula (I) or formula (II) over a similar period of time. 21. The use, method, combination for use or kit according to any one of the preceding claims, wherein the antibiotic resistance involves mutational resistance to one or more topical antibiotics that are useful for treating skin infections. 22. The use, method, combination for use or kit according to any one of the preceding claims, wherein the antibiotic resistance involves resistance to one or more isoleucine- tRNA synthetase inhibitors. 23. The use, method, combination for use or kit according to any one of the preceding claims, wherein the antibiotic resistance is resistance to mupirocin. 24. The use, method, combination for use or kit according to any one of the preceding claims, wherein the antibiotic resistance is low-level resistance to mupirocin. 25. The use, method, combination for use or kit according to any one of the preceding claims, wherein the second antibacterial agent is an antibiotic that is useful for treating a skin infection. 26. The use, method, combination for use or kit according to any one of the preceding claims, wherein the second antibacterial agent is mupirocin, fusidic acid or retapamulin. 27. The use, method, combination for use or kit according to Claim 26, wherein increase in the minimum inhibitory concentration for the mupirocin is at most one quarter of the increase in the minimum inhibitory concentration for mupirocin that would occur in the absence of the compound of formula (I) or formula (II) over a similar period of use. 28. The use, method, combination for use or kit according to any one of the preceding claims, wherein the use or method is in clinical or veterinary therapy. 29. The use, method, combination for use or kit according to any one of the preceding claims, wherein R1 is n-propylene.

30. The use, method, combination for use or kit according to any one of the preceding claims, wherein each -O-R1-N+-(R2)(R3)R4 moiety is bound to the relevant phenyl ring in either a para or meta position relative to the point of attachment to the porphyrin. 31. The use, method, combination for use or kit according to any one of the preceding claims, wherein M is selected from the group consisting of Zn (II), Cu (II), La (III), Lu (III), Y (III), In (III) Cd (II), Mg (II), Al(III), Ru(II), Ni(II), Mn(III), Fe(III) and Pd(II). 32. The use, method, combination for use or kit according to any one of the preceding claims, wherein the compound of formula (I) or (II) is 5,15-bis-[4-(3-trimethylammonio- propyloxy)-phenyl]-porphyrin dichloride, 5,15-bis-[3-(3-trimethylammonio-propyloxy)- phenyl]-porphyrin dichloride or 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- iron(III)-porphyrinium trichloride. 33. A combination comprising a compound of formula (I) or (II) as defined in Claim 1 and a second antibacterial agent selected from the group consisting of mupirocin, fusidic acid and retapamulin. 34. The combination according to Claim 33, wherein (i) the first antibacterial agent is selected from 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride; and/or (ii) the second antibacterial agent is mupirocin or retapamulin. 35. The combination according to Claim 33 or Claim 34, wherein the first and second antibacterial agents are provided together in a single pharmaceutical composition.

Description:
METHOD FOR REDUCING ANTIBIOTIC RESISTANCE EMERGENCE Field This invention relates to the new use of porphyrin compounds in suppressing the emergence of antibiotic resistance in bacteria. The invention particularly relates to the application of this use in medicine (as well as veterinary and domestic settings) where the prevalence of antibiotic resistance presents a significant threat to life. Background Bacterial infections in humans are relatively common and can range in severity from mild to life-threatening. A bacterial infection can take many different forms depending on its location, type, even the age of the affected individual. Most bacterial skin infections are caused by Staphylococcus aureus or Streptococcus pyogenes. Staphylococcus aureus is also a common cause of human bacterial infections in other parts of the body, including soft tissues, bones, bloodstream, and respiratory tract. Particular conditions that are associated with sXch bacteria include peritonitis, an infection of the inner lining of the abdomen, and impetigo. The treatment of choice for S. aureus infection is penicillin, however the history of S. aureus treatment is marked by the development of resistance to each new class of antistaphylococcal antimicrobial drugs, including the penicillins, sulfonamides, tetracyclines, glycopeptides, and others, complicating therapy. The resistance to antibiotics developed by an increasing number of microorganisms is recognised to be a worldwide health problem (Tunger et al., 2000, Int. J Microb. Agents 15: 131-135; and Jorgensen et al., 2000, Clin. Infect. Dis.30:799-808). As a consequence, the development of new approaches for killing microorganisms is urgently required. One of the most prevalent strains of resistant bacteria is methicillin-resistant Staphylococcus aureus (MRSA). Staphylococcus aureus carriage is common in human populations. Different body areas may be colonised, but these bacteria are usually found in the nose vestibule. Approximately 20%–30% of healthy adults are persistent carriers, about 50% are transient carriers, and 20% have never been colonised by S. aureus. Colonisation with S. aureus is a major risk factor for staphylococcal infections. It is estimated that approximately 80% of staphylococcal sepsis is of an endogenous origin. Nasal carriage, hair follicle infection (furuncle), or ongoing bone inflammation may appear as the source of sepsis. Staphylococcal infections may also result from direct or indirect contact with a carrier (exogenous infection) (see Kwiatkowski P. et al. , Molecules 2019, 24, 3105). Many global organizations have produced guidelines regarding decolonisation procedures. First introduced in 2016, the World Health Organization renewed their decolonisation guidelines in 2018; ‘The panel recommends that patients undergoing cardiothoracic and orthopaedic surgery with known nasal carriage of S. aureus should receive perioperative intranasal applications of mupirocin 2% ointment with or without a combination of CHG body wash (WHO, 2016; World Health Organization, 2018). In order to eliminate nasal S. aureus carriage, as well as reduce the number of endogenous infections, mupirocin (an antibiotic produced by Pseudomonas fluorescens) ointment is applied to the nasal mucosa. The effective eradication of S. aureus from the nasal vestibule reduces the amount of bacteria colonising the skin surface. This reduces the occurrence of staphylococcal post-operative wound infections and, at the same time, reduces the amount of bacteria transferred to the hands of medical personnel. When mupirocin-based nasal decolonisation regimens have been used as a routine and sustained strategy to control endemic S. aureus infection and transmission among general inpatient populations, the emergence of mupirocin resistance has been commonly, although not universally, observed. In particular, resistance seems to emerge readily in health care facilities with unrestricted policies that allow widespread mupirocin use for prolonged periods, especially when application to decubitus ulcers and other skin lesions is allowed (see Patel, J.B. et al., Clinical Infectious Diseases 2009, 49:935–41). Farrell D.J. et al., Antimicrobial Agents and Chemotherapy, Mar.2011, p.1177–1181 showed that mupirocin resistance rates are achieved rapidly following repeated exposure of bacteria to mupirocin. In contrast, minimal resistance to XF-73 (a porphyrin-containing compound also known as “Compound 10”, “exeporfinium chloride” and “5,15-bis-[4-(3- Trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride”) was observed under the same conditions. International patent application nos. WO 2004/056828, WO 2006/000765, WO 2007/074340 and WO 2010/046663 disclose the same and other porphyrin-containing compounds and demonstrate the antibacterial properties. Kwiatkowski, P. et al. (2019) Microbial Drug Resistance, 25(10), pp.1424-1429 describes the effect of subinhibitory concentrations of trans-Anethole (tA) on antibacterial properties of mupirocin against mupirocin-resistant Staphylococcus aureus strains. The authors showed that tA was able to increase the susceptibility to mupirocin in those strains. However, there is no suggestion that tA can retard or suppress the emergence of mupirocin resistance. Kwiatkowski, P. et al. (2019), Advances in Dermatology and Allergology, 36(3), pp.308– 314 discloses investigations of the effect of fennel essential oil (FEO) and trans-anethole (tA) on antibacterial activity of mupirocin against S. aureus strains. FEO and tA were both shown to influence mupirocin efficacy. There are no data showing that the combination of mupirocin and either FEO or tA is capable of limiting the emergence of mupirocin resistance. Kwiatkowski, P. et al. (2019) Molecules, 24(17), p. 3105 assessed the influence of essential oil compounds (EOCs) on the antibacterial activity of mupirocin against MupS (mupirocin-susceptible) and MupRL (induced low-level mupirocin-resistant) Staphylococcus aureus strains. Synergistic activity was identified for some combinations of EOCs and mupirocin against certain strains of S. aureus, including MupS, but there was no indication that the emergence of antibiotic resistance in MupS can be suppressed. In the era of increasing resistance to antibiotics, there remains a need for new methods of reducing the virulence of S. aureus strains and facilitating their eradication. The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Disclosure of the Invention We have now surprisingly found that certain porphyrin-containing compounds appear to possess properties which can reduce the rate at which antibacterial resistance emerges when those compounds are used as part of a co-therapy with one or more other antibacterial agents. This finding may allow for more effective treatment of bacterial infections, particularly in clinical settings, and/or help to reduce the need for the development of new therapies for bacterial infections. According to a first aspect of the invention there is provided a use of a first antibacterial agent which is a compound of formula (I) or formula (II), R 4 (R 3 )(R 2 )HN R 1 O NH N O R1 N(R2)(R3)R4 I) II) wher R 1 is a C 1 to C 6 alkylene group; R 2 , R 3 and R 4 are independently C1 to C4 alkyl; and M is a metallic element or a metalloid element, to suppress the emergence of antibiotic resistance in bacteria exposed to a second antibacterial agent. In an alternative first aspect of the invention, there is provided a method of suppressing the emergence of antibacterial resistance in bacteria exposed to a second antibacterial agent which method comprises exposing the bacteria to a first antibacterial agent which is a compound of formula (I) or formula (II) as defined herein. The use and method of the first aspect of the invention may be referred to herein as “the method of the invention”. Mutational antibiotic resistance in a bacterial population typically emerges when that population is exposed to an antibiotic and is able to survive and reproduce. If the characteristics which enabled a bacterium to survive exposure to an antibiotic are passed on to its progeny, the resulting bacterial population is likely to show an increased resistance to that antibiotic. The methods of the invention suppress the emergence of antibiotic resistance in bacteria. By the use of the term “suppress” (and related terms, such as “retard”, “reduce” or “inhibit”) we mean that the rate at which mutational antibiotic resistance emerges is reduced (or slowed) relative to the rate at which antibiotic resistance would emerge in the absence of the compound of formula (I) or formula (II) but otherwise under the same conditions. The antibacterial efficacy of a substance for a given bacterial strain may be evaluated through determining the minimum inhibitory concentration (MIC) of that substance for that strain. An increase in the resistance is evidence when the MIC of the substance increases for a bacterial strain over time. The methods of the invention have now been shown to slow (or retard) the rate of increase of the MIC for mupirocin under laboratory conditions when bacteria were repeatedly exposed to a combination of compound of formula (I) or (II) and mupirocin. It is believed that, by exposing bacteria to a combination of compound of formula (I) or (II) and a second antibiotic (e.g. mupirocin), the emergence of mutational resistance to the second antibiotic will be at least partially inhibited, and this will be useful in clinical and veterinary settings. The term “emergence” in the context of resistance refers to the increase in the MIC from an initial lower value to a higher value. A bacterial strain may be classified as resistant or susceptible to a given antibacterial agent depending on whether the MIC for that strain lies above or below an established threshold. A bacterial strain is typically said to be susceptible to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic success, and a bacterial strain is typically said to be resistant to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic failure. In some embodiments therefore, resistance of a bacterial strain to an antibacterial agent may be considered to have emerged based on whether the efficacy of the agent has dropped below a given threshold, e.g. if the MIC has increased above a given threshold. Thus, in one embodiment of the first aspect of the invention, the method or use slows the rate at which the MIC the antibacterial agent increases. The surprising finding that compounds of formula (I) and (II) may suppress the emergence of antibiotic resistance in bacteria exposed to another antibacterial agent has utility in the treatment or prevention of bacterial infections, particularly in clinical settings. According to a second aspect of the invention, there is therefore provided a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent for use in the treatment or prevention of a bacterial infection, wherein the use of the combination suppresses the emergence of antibiotic resistance. In an alternative second aspect of the invention, there is provided a method of treating or preventing a bacterial infection which method comprises administration of a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent to a subject in need of such therapy (i.e. a subject suffering from said bacterial infection or at risk of suffering from said bacterial infection) to suppress the emergence of antibiotic resistance. In a further alternative second aspect of the invention, there is provided a use of a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent in the manufacture of a medicament for treating or preventing a bacterial infection, wherein the use of the combination suppresses the emergence of mutational antibiotic resistance. The combination for use, method and use of the second aspect of the invention may also be referred to herein as “the method of the invention”, together with the first aspect of the invention. The methods of the invention involve the exposure of bacteria to a compound of formula (I) or formula (II) as defined in the first aspect. Compounds of formula (I) or formula (II) may be referred to herein as “compounds of the invention”. Unless otherwise stated, the terms C 1-q alkyl, and C 1-q alkylene, groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain. Particular groups which may be represented by R 1 include linear C 1 to C 6 alkylene group, preferably selected from the group consisting of methylene, ethylene, n-propylene and n- butylene. In a particularly preferred embodiment, R 1 is n-propylene. Each of R 2 , R 3 and R 4 may be the same or different. In preferred embodiments, R 2 , R 3 and R 4 are the same. Particular groups which may be represented by R 2 , R 3 and R 4 independently include linear C 1 to C 4 alkyl groups, preferably selected from the group consisting of methyl, ethyl and n-propyl. In a particularly preferred embodiment, R 2 , R 3 and R 4 are all the same and represent either ethyl or, particularly, methyl. Compounds of formula (I) and (II) each contain two -O-R 1 -N + -(R 2 )(R 3 )R 4 moieties. Said moieties are bound to the central porphyrin core via separate phenyl rings. A -O-R 1 -N + - (R 2 )(R 3 )R 4 moiety may be attached via any carbon atom on the requisite phenyl ring. Preferably the moiety is attached at one of the 3-, 4- or 5-positions (i.e. the meta or para positions) on the phenyl ring relative to the point of attachment to the porphyrin core. In a particularly preferred embodiment, each -O-R 1 -N + -(R 2 )(R 3 )R 4 moiety is bound to the relevant phenyl ring in the para position relative to the point of attachment to the porphyrin. The compounds of the invention carry a net positive charge, for example a charge of +2, due to the presence of the two -O-R 1 -N + -(R 2 )(R 3 )R 4 moieties. It will be appreciated by persons skilled in the art that compounds of formulae (I) and (II) may be counterbalanced by counter-anions. Exemplary counter-anions include, but are not limited to, halides (e. g. fluoride, chloride and bromide), sulfates (e.g. decylsulfate), nitrates, perchlorates, sulfonates (e. g. methane sulfonate) and trifluoroacetate. Other suitable counter-anions will be well known to persons skilled in the art. Thus, methods and uses involving pharmaceutically, and/or veterinarily, acceptable derivatives of the compounds of formulae (I) and (II), such as salts and solvates, are also included within the scope of the invention. Salts which may be mentioned include: acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. It will be further appreciated by skilled persons that the compounds of formula (I) and (II) may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The term "metallic element" is intended to include a divalent or trivalent metallic element. Preferably, the metallic element is diamagnetic. More preferably, the metallic element is selected from Zn (II), Cu (II), La (III), Lu (III), Y (III), In (III) Cd (II), Mg (II), Al(III), Ru(II), Ni(II), Mn(III), Fe(III) and Pd (II). preferably, the metallic element is Ni(II), Mn(III), Fe(III) or Pd(II). A particular trivalent metallic element that may be mentioned is Fe(III). The term "metalloid" is intended to include an element having physical and chemical properties, such as the ability to conduct electricity, that are intermediate to those of both metals and non-metals. The term "metalloid element" includes silicon (Si) and germanium (Ge) atoms which are optionally substituted with one or more ligands. It will be appreciated that the terms metallic element and metalloid element include a metal element or a metalloid element having a positive oxidation state, all of which may be substituted by one or more ligands selected from fluoro, OH, OR X wherein R X is C 1 to C 4 alkyl. Preferred compounds of formula (I) that may be used in the first and second aspects of the invention include the following: (a) 5,15-bis-[4-(3-Triethylammonio-propyloxy)-phenyl]-porphyrin dichloride; + NH N + Preferably, this compound is provided as a dichloride salt. (b) 5,15-bis-[3-(3-Trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride; NH N + Preferably, this compound is provided as a dichloride salt. (c) 5,15-bis-[4-(3-Trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride (“XF-73”); NH N + Preferably, this compound is provided as a dichloride salt. It will be appreciated that the above compounds may alternatively be provided in a metallated form, i.e. they may comprise a chelated metallic element or metalloid element within the porphyrin ring. A particular compound that may be mentioned in this respect is 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]-iron(III) -porphyrinium trichloride. In one embodiment, the compound of formula (I) or (II) is 5,15-bis-[4-(3-trimethylammonio- propyloxy)-phenyl]-porphyrin dichloride, 5,15-bis-[3-(3-trimethylammonio-propyloxy)- phenyl]-porphyrin dichloride or 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- iron(III)-porphyrinium trichloride. Compounds of formula (I) and (II) may be synthesised according to methods known in the art, e.g. as described in WO 2004/056828, WO 2006/000765 and WO 2007/074340, the contents of which are incorporated by reference. Synthetic procedures, including those for the formation of metalloporphyrins, are disclosed in The Porphyrins Volume I, Ed. David Dolphin, Academic Press, 1978 (see in particular Chapter 10 - Synthesis and Properties of Metalloporphyrins, by J. W. Buchler). Compounds of formula (I) and (II) are known to have antibacterial activity. A compound of formula (I) or (II) are therefore referred to as a “first antibacterial agent”. The methods of the invention suppress the emergence of antibacterial resistance in bacteria exposed to a second antibacterial agent. The second antibacterial agent may be a compound of formula (I) or (II) that is different from the first antibacterial agent. Preferably, the second antibacterial agent is not a compound of formula (I) or (II). The term “antibacterial agent” as used herein refers to a substance which is capable of inhibiting bacterial growth and/or reproduction, or which is capable of killing bacteria following contact with the organism in vivo or in vitro. Although the term “antibiotic” typically refers to an agent that either kills or inhibits the growth of a microorganism, the terms “antibacterial” and “antibiotic” may be used interchangeably in the context of the present invention, which principally relates to bacteria. The methods of the invention involve exposing bacteria to an antibacterial agent, e.g. a “second” antibacterial agent. While the exposure may result in the bacteria acquiring a degree of resistance to said antibacterial agent, the emergence of that resistance is suppressed (i.e. it is slowed or retarded) by these methods. The methods are particularly suited to suppressing resistance to topical antibiotics, particularly antibiotics that are effective in controlling bacterial infections typically associated with skin. Thus, in one embodiment of the methods of the invention, the antibacterial agent (e.g. the “second” antibacterial agent) is a topical antibiotic. In another embodiment, the second antibacterial agent is an antibiotic that is useful for treating a skin infection. The form of resistance for which emergence is suppressed by the methods of the invention may be resistance to one of the antibacterial agents (particularly the second antibacterial agent) to which the bacteria are exposed. However, it is possible that the emergence of resistance to other antibacterial agents may also be suppressed, e.g. agents that are structurally or functionally similar to the antibacterial agent to which the bacteria are exposed. The methods of the invention may be particularly effective in suppressing the emergence of mutational resistance to topical antibiotics, such as antibiotics that are useful for treating skin infections. The methods of this invention are particularly suited to use with topical therapies as it is easier to ensure that the compound of formula (I) or (II) is delivered to the site of the infection at the same time that the bacteria are exposed to the second antibacterial agent. Particular topical antibiotics that may be mentioned in this respect include retapamulin, fusidic acid and, preferably, mupirocin. In particularly preferred embodiments, the methods of the invention suppress resistance to one or more isoleucine-tRNA synthetase inhibitors, particularly mupirocin. Different forms of mupirocin resistance are known, and they may be distinguished according to their genetic nature. High-level mupirocin resistance is usually associated with the presence of the mupA gene, which encodes an alternative IleS enzyme [Hurdle JG, O'Neill AJ, Ingham E, Fishwick C, Chopra I. 2004. Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modelling techniques. Antimicrob. Agents Chemother.48:4366-4376]. Low-level mupirocin has also been described and is usually due to the selection of specific mutation(s) within the intrinsic ileS gene (Hurdle et al. ibid.; Antonio M, McFerran N, Pallen MJ.2002. Mutations affecting the Rossman fold of isoleucyl-tRNA synthetase are correlated with low-level mupirocin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 46:438-442). In a particular embodiment, the antibiotic resistance is low-level resistance to mupirocin. We have shown that a reduction in the emergence of mupirocin resistance is achieved when mupirocin is administered to Staphylococcus aureus in combination with a porphyrin- containing compound (5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]-porphyri n dichloride, referred to herein as “XF-73”). Without wishing to be bound by theory, it is believed that the methods of the invention are particularly suited to suppressing resistance emergence in mupirocin-susceptible bacteria. Examples of Gram-positive and Gram- negative bacteria that are susceptible to mupirocin are disclosed in Sutherland R, et al. Antimicrob. Agents Chemother.1985;27(4):495–498, therefore the invention is particularly suited to suppressing resistance emergence in those bacteria. In one embodiment, the bacteria are selected from, but not limited to, the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus spp.. Furthermore, it is believed that the methods of the invention are particularly suited to suppressing resistance emergence in mupirocin-susceptible bacteria that are also susceptible to XF-73 and/or similar porphyrin-containing compounds. Therefore, in a further embodiment, the bacteria are selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus spp. Particular bacteria that may be mentioned in the context of the methods of the present invention are Staphylococcus sp. and Streptococcus sp., particularly Staphylococcus aureus and Streptococcus pyogenes. The methods of the invention are particularly suitable for suppressing resistance emergence in bacteria which have already developed resistance to conventional antibiotic treatments. By this, we mean that the methods are particularly suitable for suppressing resistance emergence in bacteria that are resistant to one or more other antibiotics, i.e. an antibiotic that is different from the “first” and “second” antibiotics referred to hereinabove. The studies described herein demonstrate that suppression of the emergence of resistance can be achieved in methicillin-resistant Staphylococcus aureus (MRSA). In one embodiment, the bacterial infection is a methicillin-resistant Staphylococcus aureus or Streptococcus pyogenes infection. In the methods of the first aspect of the invention, the bacteria in which resistance emergence is suppressed are exposed to at least two antibacterial agents. By the use of the term “exposed” in this context, we mean that the bacteria are brought into physical contact with said antibacterial agent. The precise method by which physical contact is achieved may depend upon the location of the bacteria. For example, in a dermal bacterial infection the bacteria may be located within the dermis. Exposure may be achieved by application of the antibacterial agent to the surface of the skin above the site of the infection, so that the agent may then penetrate the epidermis and thereby reach the bacteria. The methods of the invention may be useful in suppressing the emergence of resistance arising during the treatment or prevention of an infection in a subject or a patient. As used herein, references to “patients” will refer to a living subject being treated, including mammalian (in particular, human) patients, and as such “patients” may also be referred to as “subjects”, and vice versa. References to “patients” (and therefore also to “subjects”) also should be considered to refer to individuals displaying no symptoms of the relevant condition, for whom methods of the invention may be used as a preventative or prophylactic measure (as defined herein). For the avoidance of doubt, references to “patients” may also include references to animals, such as non-mammalian animals (e.g. birds) and, particularly, mammalian animals (e.g. cats, dogs, rabbits, rodents, horses, sheep, pigs, goats, cows, primates, and the like). Thus, the methods of the invention may be used in either a clinical or veterinary setting. The methods of the invention may involve administration of the compound of formula (I) or formula (II) to a subject (e.g. a human patient) suffering from a topical bacterial infection, e.g. as part of a method of treating that infection. A subject is considering to be suffering from a topical bacterial infection when the presence of the bacteria is causing damage to body tissues. This is usually associated with acute inflammation at the site of infection. The methods of the invention are also useful in preventative measures, particular where a subject does not appear to have an infection, but has an increased susceptibility to the acquisition of an infection, e.g. as a result of colonisation. For example, around one third of the general population is thought to be colonised with Staphylococcus aureus, with the pooled prevalence of MRSA colonisation being around 1.3% [Salgado CD, et al. Clin. Infect. Dis.2003;36:131–9]. In humans, the most common site of Staphylococcus aureus colonisation is the anterior nares, though such bacteria are also commonly present in the throat, axilla, rectum, groin, and perineum. The potential for antibiotic resistance to emerge is therefore high in subjects that are undergoing antibiotic therapy. The methods of the invention may be useful in preventing a subject (e.g. a human) that is colonised with bacteria and undergoing antibiotic therapy from developing a bacterial infection, particularly an antibiotic-resistant infection. References herein to a subject that is “at risk” of suffering from a bacterial infection include references to a subject that is colonised but not infected with said bacteria. The subject may be colonised with or infected with any of the bacteria described herein. In one embodiment, the bacteria are Staphylococcus sp. or Streptococcus sp., particularly Staphylococcus aureus or Streptococcus pyogenes The methods of the invention may therefore be used to suppress the emergence of antibiotic resistance in both therapeutic and preventative contexts, i.e. as part of either the treatment or prevention of a bacterial infection. Thus, in the first aspect of the invention, the compound of formula (I) or formula (II) may be administered to a subject suffering from a bacterial infection or colonised with bacteria. Preferably, the compound of formula (I) or formula (II) and the second antibacterial agent are administered to a subject suffering from a bacterial infection or colonised with bacteria, and they may be administered separately or simultaneously. The skilled person will understand that references herein to the “treatment” of a particular condition (or, similarly, to “treating” that condition) take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition. The skilled person will understand that references herein to “prevention” of a particular condition (and, similarly, to “preventing” that condition) take their normal meanings in the art. In particular, these terms may refer to achieving a reduction in the likelihood of developing the relevant condition or symptoms associated with the relevant condition (for example, a reduction of at least 10% when compared to the baseline level, such as a reduction of at least 20% or, more particularly, a reduction of at least 30%). Similarly, the term “preventing” may also be referred to as “prophylaxis” of the relevant condition, and vice versa. The emergence of resistance may be detected and quantified through measuring the minimum inhibitory concentration (MIC) and observing an increase therein. The MIC for an antimicrobial agent against a specific microorganism is defined as the minimum concentration of an antibacterial agent at which no apparent visible growth of the organism is observed (FDA definition of Minimum Inhibitory Concentration). MICs are typically determined using concentrations derived traditionally from serial twofold dilutions (M07Ed11. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eleventh edition. Clinical and Laboratory Standards Institute). If resistance emergence in a microorganism is suppressed, the MIC for a given antibacterial agent (i.e. the second antibacterial agent) against the microorganism may remain unchanged or may increase by an amount that is less than would otherwise occur. For the methods of the invention, the increase over a given period of time will be considered to be reduced if it is lower (e.g. reduced by 20%, such as reduced by 50%) in comparison to the increase in MIC for the second antibacterial agent that occurs in the absence of the compound of formula (I) or formula (II) over a similar period of time. The methods of the invention may be particularly suitable for use with subjects that have an increased risk of suffering from a bacterial infection. A subject may be considered to have an increased risk of suffering from a bacterial infection if that subject is due to undergo a surgical or cosmetic procedure. Particular subjects that may be mentioned in this respect include subjects that are due to undergo a surgical or cosmetic procedure and that are colonised with pathogenic bacteria, such as Staphylococcus sp. or Streptococcus sp. Thus, in one embodiment of the invention, the compound of formula (I) or formula (II) is administered to a subject has an increased risk of suffering from a bacterial infection, e.g. an infection by Staphylococcus sp. or Streptococcus sp. The methods of the invention may be advantageously used in surgical or cosmetic procedures which involve penetration of the skin or the treatment of a wound or burn. Such procedures would be known to the skilled person and include procedures requiring the use of a catheter, suture or surgical drain. Certain clinical procedures involve the penetration of the skin using a catheter in order to transfer fluid into and out of the body. One example of this is peritoneal dialysis which involves the insertion of a catheter through the abdominal wall for fluid exchange within the abdomen. The catheter may remain in place for an extended period, typically several months, and the risk of an infection arising from the presence of the catheter is significant. Infections that most commonly arise in subjects receiving peritoneal dialysis include exit site infections, i.e. infections in the skin region around the catheter, and infections in the abdominal cavity which may cause peritonitis, i.e. inflammation of the peritoneum. The methods of the invention may therefore be particularly useful in the prevention of an exit site infection or peritonitis resulting from peritoneal dialysis. The methods may also be useful in the context of wound healing, e.g. arising from surgery or an injury, where the break in the skin increases the subject’s susceptibility to acquiring a bacterial infection. The methods of the invention may therefore be particularly useful in the prevention of post-operative wound infections and in treating burn wounds, particularly staphylococcal infections. Cosmetic procedures which may be mentioned in this respect include body piercings, particularly nose piercings, and procedures involving the insertion, adjustment or removal of a cosmetic implant. Bacteria, such as Staphylococcus aureus, that colonise nasal passages can also provide a source of infection for patients. Therefore, patients that undergo surgery may benefit from prior bacterial nasal decolonisation as this will reduce the likelihood of an infection arising that will require medical intervention. Decolonisation may be performed using any method known to a medical professional, e.g. using a nasal ointment, with the aim of significantly reducing the numbers of bacteria resident in or on the body (particularly in the nasal passages). Decolonisation is commonly recommended when a patient is known or suspected to be colonised with a strain of antibiotic-resistant bacteria, such as methicillin- resistant Staphylococcus aureus (MRSA). Decolonisation may also be recommended when a patient has an increased risk of infection due to another medical condition, such as cancer, diabetes or a condition that weakens the immune system. Decolonisation using the method of the invention may not only significantly reduce the quantity of bacteria present but also reduce the likelihood of bacteria acquiring further antibiotic resistance and remaining in or on the patient. This benefits the patient and reduces the risk of the infection (which may include a resistant bacterial strain) being spread among the wider population. Thus, in one embodiment, the method of the invention, particularly a method of preventing a bacterial infection, involves nasal decolonisation of Staphylococcus sp. Preferably the nasal decolonisation is achieved through the simultaneous administration of the compound of formula (I) or formula (II) and the second antibacterial agent to the patient. Decolonisation, particularly nasal decolonisation, may be performed for patients regardless of whether they are due to undergo a surgical procedure. Decolonisation may be desired as part of a wider decolonisation program to reduce the prevalence of bacterial infections, particularly antibiotic-resistant infections such as MRSA, in patients or to reduce the spread of such strains in medical practices (particularly hospitals), care homes, veterinary surgeries. Thus, in a further embodiment of the second aspect, the invention relates to a method of preventing a bacterial infection which method comprises administration of a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent to a subject colonised with bacteria (e.g. MRSA) to decolonise the subject. Mupirocin is commonly used for bacterial decolonisation, particularly MRSA decolonisation. Commercially available mupirocin-containing products include Bactroban® Nasal Ointment which contains mupirocin calcium at a concentration equivalent to 2% w/w mupirocin free acid ointment. This is a paraffin-based nasal ointment containing a glycerin ester (typically bis-diglyceryl polyacyladipate-2). Other mupirocin-containing products include Bactroban® Ointment which is indicated for the topical treatment of impetigo due to Staphylococcus aureus and Streptococcus pyogenes, and Bactroban® Cream which is indicated for the treatment of secondarily infected traumatic skin lesions. Other commercially available antibiotics which may be used include fusidic acid and retapamulin. Examples of such products include Fucidin (fusidic acid) which is a 20 mg/g cream, and Altabac (retapamulin) which is a 1% ointment. Antibiotic formulations known to the person skilled in the art, including the mupirocin, fusidic acid and retapamulin formulations disclosed here, may be used in the methods of the invention, e.g. as a source of the (second) antibacterial agent. The compounds of formula (I) and (II) and the second antibacterial agent will generally be administered in the form of one or more pharmaceutical formulations in admixture with a pharmaceutically acceptable excipient, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable excipients may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable excipients may also impart an immediate (e.g. rapid), or a modified (e.g. delayed), release of the active ingredients. Suitable pharmaceutical formulations may be commercially available or otherwise be described in the literature (see, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and Martindale – The Complete Drug Reference (35 th Edition), and the documents referred to therein), the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques. Suitable pharmaceutical formulations for use with the compounds of the invention are also described in International patent application no. WO 2006/000765. For example, for application topically, e.g. to the skin or a wound site, the compounds (e.g. the compound of formula (I) or (II) and the second antibacterial agent) can be administered (separately or together) in the form of a lotion, solution, cream, gel, ointment or dusting powder (for example, see Remington, supra, pages 1586 to 1597). Thus, the compounds can be formulated as a suitable ointment containing the active compound(s) suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream containing the active compound(s) suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, e-lauryl sulphate, an alcohol (e.g. ethanol, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol) and water. Alternatively, they can be formulated as a suitable gel containing the active compound(s) suspended or dissolved in, for example, a mixture of one or more of the following: a natural polymer (e.g. a protein (such as gelatin, casein, collagen, and egg whites) or a polysaccharide (such as guar gum, acacia, tragacanth, bug bean gum, pectin, starch, xanthan gum, dextran, succinoglucon)), a semisynthetic polymer (e.g. a cellulose subordinate (such as carboxymethyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose and, particularly, hydroxypropylcellulose), magnesium aluminium silicate or sodium alginate), a synthetic polymer (e.g. a Carbopol® (now known as a carbomer), a poloxamer, a povidone derived thickener (e.g. Povidone K90) or polyvinyl alcohol), an emulsified gel (e.g. Sepineo P600) and water. In a preferred embodiment, the medicament (e.g. lotion, solution, cream, gel or ointment) is water-based. The medicament comprising the compound of formula (I) or (II) may also be administered intranasally or by inhalation and may be conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2- tetrafluoroethane (HFA 134A 3 or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA 3 ), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of formula (I) or (II) and a suitable powder base such as lactose or starch. The methods of the invention may involve exposing bacteria to both a first and second antibacterial agent, as defined herein. The use of such agents in combination is found to particularly effective at suppressing the emergence of antibacterial resistance. The first and second antibacterial agents may be administered concomitantly or sequentially. In a preferred embodiment, the first and second antibacterial agents are administered simultaneously. The first and second antibacterial agents may also be provided in a single pharmaceutical composition or may be provided in separate pharmaceutical compositions. References herein to “combinations” therefore include references to a single formulation which contains both the first and second antibacterial agent, and also to the provision of the first and second antibacterial agents in different formulations. According to a third aspect of the invention, there is therefore provided a combination comprising first antibacterial agent which is a compound of formula (I) or formula (II) as defined herein, and a second antibacterial agent. Said combination may be useful in the treatment or prevention of a bacterial infection, wherein the use of the combination suppresses the emergence of antibiotic resistance. The first and second antibacterial agents may be provided in a single pharmaceutical composition or may be provided in separate pharmaceutical compositions. Particular first antibacterial agents that may be mentioned in this respect include 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride. Particular second antibacterial agents that may be mentioned in this respect include retapamulin and mupirocin. In one embodiment, the combination may comprise a first antibacterial agent selected from 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride, and a second antibacterial agent selected from fusidic acid, retapamulin and mupirocin, optionally wherein the first and second antibacterial agents are provided in a single pharmaceutical composition. Further, in another aspect of the invention, there is provided a kit-of-parts comprising components: (A) a pharmaceutical formulation comprising a compound of formula (I) or (II), and optionally one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising the second antibacterial agent, such as mupirocin, and optionally one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other. Said kit-of-parts may be useful in the treatment or prevention of a bacterial infection, wherein the use of the kit suppresses the emergence of antibiotic resistance. For the avoidance of doubt, all embodiments and particular features described in relation to previously mentioned aspects of the invention (and combinations thereof) will also apply to the kits-of-parts described herein. By “administration in conjunction with” (and similarly “administered in conjunction with”) we include that respective formulations comprising the first and second antibacterial agents are administered, sequentially, separately or simultaneously, as part of the same medical intervention. Therefore, in relation to the present invention, the term “administration in conjunction with” (and similarly “administered in conjunction with”) includes that the two active ingredients (i.e. the compound of formula (I) or (II), and the second antibacterial agent) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising a compound of formula (I) or (II), or a formulation comprising a second antibacterial agent are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Preferably the first and second antibacterial agents are administered together. Further, in the context of the present invention, the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component. One example of this is a treatment regime which involves administration of mupirocin alongside administration of XF-73, with both administration regimes co-existing for a continuous period of at least 24 hours. Mupirocin is typically administered up to 3 times daily and XF- 73 is typically administered up to four times daily, consequently the time points when individual doses of the two components are administered may not always coincide. When used in the context of the present invention, the terms “administered simultaneously” and “administered at the same time as” include such administration regimes. In one embodiment, the individual doses of a compound of formula (I) or (II) and a second antibacterial agent are administered within 1 hour (e.g. within 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other. As used herein, references to “sequential administration” may refer to separate administration of the therapeutic agents as part of the same medical intervention (e.g. within four hours, such as within two hours or, particularly within one hour, of each other). Thus, in relation to a further aspect of the invention, there is also provided a kit-of-parts comprising: (I) one of components (A) or (B) as described in the previous aspect of the invention; and (II) instructions to use that component in combination with the other of the two components, for use in treating or preventing a bacterial infection, wherein the use suppresses the emergence of antibiotic resistance. As described herein, pharmaceutical formulations (including those containing more than one active ingredient as described herein) may be prepared using techniques known to those skilled in the art. Similarly, a kit-of-parts (as described in herein) may be prepared using techniques known to those skilled in the art. Depending on the patient to be treated, the route of administration and the severity of the condition, the first and second antibacterial agents may be administered at varying therapeutically effective doses (to the relevant patient in need thereof). Suitable doses may be determined by the skilled person using routine techniques, such as by routine dose titration studies and the like. When used in the context of the present invention, the terms “therapeutically effective doses” (and similar terms such as “effective amount”) refer to an amount that is effective to suppress resistance emergence. Similarly, the amount of the first and second antibacterial agents included in the relevant pharmaceutical formulations may be determined based on the desired dosage of the first or second antibacterial agent, as appropriate, the ease of formulation and the route of administration (which may in turn determine the availability of the first or second antibacterial agent for systemic absorption). The medicament comprising the compound of formula (I) or (II) may be formulated at various concentrations, depending on the efficacy/toxicity of the compound being used and the indication for which it is being used. Preferably, the medicament comprises the compound at a concentration of from about 0.1 to about 5,000 mg/L, such as from about 0.1 to about 2,000 mg/L (e.g. about 0.1 to about 500 mg/L). Topical formulations may be administered directly at the site of need using an amount conventional for a topical ointment or other topical formulation. Doses may be repeated as necessary, such as in the form of periodic, sequential applications. For example, the doses may be administered once or twice per day for several days (e.g. from 1 to 21 days, such as from 3 to 14 days, preferably for around 5 to 10 days). In one embodiment, the compound of formula (I) or (II) and the second antibacterial agent are administered together twice daily for five days. The preferred dosage frequency for the second antibacterial agent is the dosage frequency prescribed in approved commercial product labels. For example, Fucidin (fusidic acid) may be provided as a 20 mg/g cream which is administered to affected skin three to four times per day. Retapamulin may be provided as a 1% ointment which is administered to affected skin twice daily for five days. Mupirocin ointment may be provided as a 20 mg/g ointment which is administered to affected skin three times per day for up to ten days. Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains at least 1 mg of a compound of formula (I) or (II) for delivery to the patient. It will be appreciated that the overall dose with an aerosol will vary from patient to patient and from indication to indication, and may be administered in a single dose or, more usually, in divided doses throughout the day. Mupirocin nasal ointment may be provided as a 2 wt% ointment which is administered to the nose (0.5g of ointment administered to each nostril) twice daily for 5 days. The dosage frequency of the compound of formula (I) or (II) may be matched with that of the second antibacterial agent, i.e. in line with any of the dosage frequencies described here, or vice versa. For the avoidance of doubt, the skilled person will understand that dose of compounds of formula (I) or (II) administered (e.g. to a human) should be sufficient to effect the desired therapeutic response or preventative effect within (and over) a reasonable timeframe. In any event, the skilled person will be able to determine routinely the actual dosage which will be most suitable for an individual patient. While the above-mentioned dosages are exemplary of the average case, there can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of the invention. Administration of each of the first and second antibacterial agents may be intermittent (e.g. through periodic application of an ointment), or may be provided in the form of a single dose (e.g. by a single application of an ointment). The dosage form may also be determined by the timing and frequency of administration, and vice versa. Where the first and second antibacterial agents are not provided in the same formulation, they may be administered at different times and/or at different frequencies. For example, the first antibacterial agent may be administered twice per day, whilst the second antibacterial agent is administered once per day. For the avoidance of doubt, wherever the word “about” is employed herein, for example in the context of amounts (e.g. doses of active ingredients), it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein. For the avoidance of doubt, unless otherwise stated, all embodiments and particular features described in relation to particular aspects of the invention (and combinations thereof) will also apply to all other aspects of the invention, as appropriate. Figures Preferred, non-limiting embodiments of the invention will now be described by way of example, with reference to the accompanying drawings in which: Figure 1 shows a graphical representation of mupirocin and mupirocin–XF-73 MIC values by day during serial passaging (log 2 MIC scale). XF-73 was present at a fixed 0.12 mg/L, where indicated. Figure 2 shows a graphical representation of mupirocin and mupirocin–XF-73 MIC values by day during serial passaging (linear MIC scale). XF-73 was present at a fixed 0.12 mg/L, where indicated. Figure 3 shows a comparison of fold increases in mupirocin MIC values of purified terminal strains after serial passaging. Two colonies were purified and tested from each terminal culture (i.e., 20 total MIC values are reported from 10 terminal cultures; see Table 3). The mupirocin MIC of the parent isolate was 0.12 mg/L. Examples Example 1: Reduction of mupirocin resistance emergence using XF-73 The ability of sub-MIC levels of 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride (referred to here as XF-73) to reduce the in vitro development of mupirocin resistance when a methicillin-resistant Staphylococcus aureus (MRSA) clinical isolate was subjected to serial passaging in the presence of mupirocin–XF-73 combinations was evaluated. Methods Mupirocin resistance development in the presence or absence of XF-73 was studied in an MRSA isolate using serial passaging methodology. The isolate did not carry the plasmid- borne mupA gene that is associated with mupirocin resistance. Although the current CLSI M100 document does not provide interpretive criteria for mupirocin, it states that S. aureus LVRODWHV^ZLWK^PXSLURFLQ^0,&^ YDOXHV^ ^^^2 mg/L display high-level mupirocin resistance, which is usually associated with the presence of the plasmid-borne mupA resistance gene that encodes an alternative IleS enzyme [Hurdle et al., ibid.]. Low-level mupirocin resistance (MIC, 8-256 mg/L) has also been described, and is usually due to the selection of various mutations within the intrinsic ileS gene [Hurdle et al., ibid.]. This study was concerned with the development of low-level mupirocin resistance. Isolates were tested for antimicrobial susceptibility using broth microdilution methodology per CLSI guidelines [CLSI.2019 ibid.; CLSI. 2018. M07Ed11. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eleventh edition. Clinical and Laboratory Standards Institute, Wayne, PA]. The testing medium was cation-adjusted Mueller-Hinton broth (CAMHB). The inoculum density during susceptibility testing was monitored by bacterial colony counts. Effect of XF-73 on Mupirocin MIC Values: The initial modal MIC values for mupirocin and XF-73 that were measured for isolate #1034046 were 0.12 mg/L and 0.25 mg/L, respectively. Preliminary experiments demonstrated that the mupirocin MIC value decreased to 0.06 mg/L when combined with XF-73 at 0.12 mg/L (i.e., half of the apparent MIC value for XF-73 alone), and that robust overnight growth was usually obtained at all concentrations below the MIC value. Therefore, to maximize the effect of XF-73 during serial passaging experiments, mupirocin serial dilutions were combined with a fixed concentration of 0.12 mg/L XF-73. Serial Passaging with Mupirocin and Mupirocin–XF-73 Combinations: A total of 5 independent cultures of MRSA isolate #1034046 were subjected to serial passaging in the presence of increasing concentrations of mupirocin, and an additional 5 independent cultures were subjected to serial passaging in the presence of increasing concentrations of mupirocin with XF-73 present at a fixed concentration of 0.12 mg/L. On each day of serial passaging, the MIC value for each independent culture was recorded from the previous day’s serial passaging panel. The material from the well 1 dilution below the MIC value was harvested and used to inoculate 5.5 mL of CAMHB, which was grown for ~3 hours at 35°C with aeration. Each culture was then diluted and added to the next serial passaging panel such that a cell concentration of ~5 x 10 5 CFU/mL was achieved in each well. The serial passaging panel was then grown at 35°C without aeration for 16-20 hours. Multiple inocula from the isolate were independently passaged daily for 50 days in the presence of mupirocin or a combination of mupirocin plus a sub-MIC concentration of XF- 73. MIC Testing of Terminal Isolates from Serial Passaging: Samples of the 10 terminal, independently passaged cultures of MRSA #1034046 were streaked onto compound-free agar plates. The MIC values for mupirocin, XF-73, and oxacillin were measured for each of the purified, duplicate samples of the 10 terminal cultures. Results Resistance Selection During Serial Passaging: Mupirocin: The MIC values that were observed for 5 independent cultures of MRSA #1034046 during serial passaging in the presence of mupirocin are shown in Table 1 and Figures 1 and 2. The mupirocin MIC values generally increased in a stepwise manner for each independent culture as the serial passaging progressed. As would be expected from randomly arising mutational events, however, the appearance and magnitude of the increased mupirocin MIC values that were observed varied for each culture (Figures 1 and 2). The terminal cultures exhibited mupirocin MIC values that were 4- to 128-fold higher than the starting isolate, and these increased MIC values remained stable after the terminal cultures were purified on drug-free medium (Table 3 and Figure 3). Both strains that were purified from each terminal culture exhibited similar MIC values, which suggested that each terminal culture was relatively homogenous in phenotype. The XF-73 MIC values exhibited by the purified terminal strains were identical or 1 dilution lower than the parent isolate (Table 3). Mupirocin and XF-73 (at a fixed concentration of 0.12 mg/L): The MIC values that were observed for 5 independent cultures of MRSA #1034046 during serial passaging in the presence of mupirocin–XF-73 (fixed 0.12 mg/L) are shown in Table 2 and Figures 1 and 2. Unlike the results obtained with mupirocin alone, the mupirocin–XF-73 (fixed 0.12 mg/L) MIC values varied little during the course of the serial passaging. The modal MIC value for mupirocin–XF-73 (fixed 0.12 mg/L) against the parental isolate #1034046 was 0.06 mg/L and the majority of MIC values that were measured during serial passaging were within 1 dilution of the starting modal MIC. The cultures with the highest terminal MIC values for the combination were #2 (0.25 mg/L) and #4 (0.25 mg/L) (Table 2). Both strains that were purified from each terminal culture exhibited similar MIC values, which suggested that each terminal culture was relatively homogenous in phenotype. The mupirocin MIC values against the purified terminal strains were identical to the parent isolate for 1 strain, 2-fold higher for 5 strains, 4-fold higher for 2 strains, and 8-fold higher for 2 strains (Table 3 and Figure 3). The XF-73 MIC values exhibited by the purified terminal strains were identical to the parent isolate (Table 3). Table 1 - Mupirocin MIC values by day for serial passaging of Staphylococcus aureus #1034046 MIC (mg/L) Passage day Replicate 1 Replicate 2 Replicate 3 Replicate 4 Replicate 5 MIC (mg/L) Passage day Replicate 1 Replicate 2 Replicate 3 Replicate 4 Replicate 5 Table 2 - Mupirocin–XF-73 (fixed 0.12 mg/L) MIC values by day for serial passaging of Staphylococcus aureus #1034046 MIC (mg/L) Passage day Replicate 1 Replicate 2 Replicate 3 Replicate 4 Replicate 5 MIC (mg/L) Passage day Replicate 1 Replicate 2 Replicate 3 Replicate 4 Replicate 5

) L / n i l 4 4 4 4 4 4 4 4 4 4 9 2 Conclusions Genetic Nature of Mupirocin Resistance: Low-level mupirocin is usually due to the selection of specific mutation(s) within the intrinsic ileS gene (Hurdle et al., ibid.; Antonio et al., ibid.). It is also possible to obtain high-level mupirocin resistance in vitro during serial passaging [Farrell DJ, Robbins M, Rhys-Williams W, Love WG.2011. Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus isolates during a 55-passage study. Antimicrob. Agents Chemother. 55:1177-1181], but the significance of this observation is unknown. This study was concerned with the development of low-level mupirocin resistance, because no source of the mupA gene was present. It seems likely that many or all of the strains with increased mupirocin MIC values that were identified in this study contain mutation(s) in the ileS gene, but this was not directly examined. Mupirocin Resistance Development During Serial Passaging: Kosowska-Shick et al. ibid. examined the in vitro development of mupirocin resistance during serial passaging in 12 different S. aureus strains. In their study, the mupirocin MIC values of the terminal strains increased by 4- WR^^^^^-fold compared to their respective starting strains. Farrell et al. ibid. carried out a similar serial passaging study with mupirocin and 4 MRSA strains and observed terminal mupirocin MIC values that increased by 128- to 4,096-fold compared to the respective parental strains. In this study, MRSA isolate #1034046 was serially passaged in the presence of mupirocin, which increased the mupirocin MIC values of the terminal strains by 4- to 128-fold (Figure 3). Importantly, although the mupirocin MIC values of the terminal, purified strains passaged in the presence of mupirocin–XF-73 combinations generally also increased, the magnitude of the effect was significantly smaller (ч2- to 8-fold; Figure 3). The presence of XF-73 therefore helped suppress the development of mupirocin resistance when isolate #1034046 was subjected to 50 days of serial passaging in vitro. Although XF-73 was administered at sub-MIC levels, it is expected that the use of higher concentrations would still have achieved the effect of suppressing the development of mupirocin resistance. Exposure to Sub-MIC Levels of XF-73 Did Not Lead to the Development of XF-73 Resistance During Serial Passaging: Farrell et al. ibid. examined the development of resistance in serial passaging experiments using 4 MRSA strains exposed to XF-73 alone, and they observed that the terminal XF-73 MIC values increased by only 2- to 4-fold compared to the respective starting strains. Consistent with the findings of Farrell et al. ibid., we did not observe any increase in XF-73 MIC values when MRSA isolate #1034046 was serially passaged in the presence of mupirocin–XF-73 (fixed 0.12 mg/L).