EP4615855A2 - New antibacterial products - Google Patents

Abstract

The invention provides novel antibacterial compounds of formula I as defined herein. (I) The invention also provides the use of such compounds in treating or preventing bacterial infections, and processes for their synthesis.

Description

NEW ANTIBACTERIAL PRODUCTS Field of the Invention This invention relates to a series of novel compounds, methods of making said compounds and their use as antibacterial agents. The compounds have been developed as readily-accessible synthetic analogues that are related to the depsipeptide antibacterial known as Novo29. The novel compounds display potent antibacterial activity and may be useful in treating and preventing bacterial infections. Background We are currently facing a worldwide pandemic of multidrug resistant bacteria, arising from the long-term use of antibacterials. Antibacterial over-availability and poor prescribing practices have allowed exposure to sub-optimal concentrations of antibacterial drugs, promoting the evolution of environmental resistance mechanisms in bacteria. Increasing bacterial resistance against currently used antibiotics and the lack of new antibiotics to combat multi-drug resistant bacterial pathogens are significant challenges to global health and wealth (estimated 4.9 million deaths in 2019 which is more than total number of deaths due to COVID-19 in 2020, Lancet 2021). Multi-drug resistant bacterial pathogens, such as Methicillin resistant Staphylococcus aureus (MRSA), Enterococcus spp. (vancomycin-resistant enterococci, VRE), Mycobacterium tuberculosis, are listed by the World Health Organisation (WHO) as “high priority pathogens” due to increasing mortality and healthcare burden. There is therefore a continuing need to develop new compounds and strategies for combating unwanted bacterial growth, particularly in bacteria that are resistant to existing drugs. Novo29 is a recently-discovered depsipeptide antibiotic (see international patent publication no. WO 2018/187173). Novo29 is isolated from Beta-Proteobacteria. Novo29's unusual structure comprises a mixture of L- and D-amino acid residues, along with an asparagine residue. The manufacture of Novo29 in a commercial scale is difficult and expensive, in part due to the presence of the hydroxy-asparagine residue. The inventors have now found a new range of analogues that is easily-accessible and displays potent antimicrobial activity, and have developed robust processes for their synthesis. The listing or discussion of an apparently prior published document in this specification should not necessarily be taken as an acknowledgement that the disclosure of the document is part of the state of the art or is common general knowledge. Description of the Invention According to a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically-acceptable salt or solvate thereof, wherein: R¹ represents H, C_1-4 alkyl, benzoyl -C(O)C_1-8 alkyl or -C(O)OC_1-8 alkyl, wherein the latter four groups are optionally substituted by one or more substituents selected from the group consisting of halogen (e.g. F or Cl atoms) and -NH₂; R^1a represents H or C_1-4 alkyl; AA¹ represents a proteinogenic or non-proteinogenic amino acid; or R¹, R^1a and AA¹ together represent a -C(O)C_1-8 alkyl group in which the C_1-8 alkyl portion is optionally substituted by one or more substituents selected from -NH₂ and phenyl; AA² _, AA³, and AA⁴ each independently represents a proteinogenic or non-proteinogenic amino acid; R², R³ and R⁴ each independently represents a proteinogenic or non-proteinogenic amino acid side chain; R⁵ represents -C(O)- or -SCH₂-; R⁶ represents hydrogen or C_1-4 alkyl; and Z is -O-, -NH- or -S-. According to a particular embodiment of the first aspect of the invention, there is provided a compound of formula IA, or a pharmaceutically-acceptable salt or solvate thereof, wherein: R¹ represents H, C_1-4 alkyl, benzoyl or -C(O)C_1-8 alkyl, wherein the latter three groups are optionally substituted by -NH₂; AA¹ represents a proteinogenic or non-proteinogenic amino acid; or R¹ and AA¹ together represent a -C(O)C_1-8 alkyl group in which the C_1-8 alkyl portion is optionally substituted by one or more substituents selected from -NH₂ and phenyl; AA², AA³, and AA⁴ each independently represents a proteinogenic or non-proteinogenic amino acid; R², R³ and R⁴ each independently represents a proteinogenic or non-proteinogenic amino acid side chain; R⁵ represents -C(O)- or -SCH₂-; R⁶ represents hydrogen or C_1-4 alkyl; and Z is -O-, -NH- or -S-. Such compounds, salts and solvates are referred to hereinafter as the “compounds of the invention”. By “pharmaceutically-acceptable salt” we mean an acid or base salt suitable for use in pharmaceuticals. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium. Particularly preferred salts include those derived from acetic, trifluoroacetic, hydrochloric, citric and tartaric acids. By “solvate” we mean a solid form wherein the compound is associated with one or more solvent molecules. The term solvate includes hydrates and other solvates of pharmaceutically-acceptable solvents. A preferred solvent for solvate formation is DMSO. By “amino acid” and “residue” (for example phenylalanine “residue”), unless indicated otherwise, we mean the dehydrated portion of an amino acid present in polypeptide chains and represented by the following formula wherein S. C. represents an amino acid side chain. For the avoidance of doubt, the term “amino acid” includes non-proteinogenic amino acids unless otherwise specified. In certain cases, for example amino acids represented by AA¹, the hydrogen atom attached to the nitrogen atom in the structure above may be replaced with a C_1-4 alkyl group as represented by R^1a. By “amino acid side chain” or “side chain of an amino acid” we mean the group attached to the position Į (alpha) to the carboxyl and amino groups in Į-amino acids, including non-proteinogenic Į-amino acids and particularly proteinogenic amino acids. The skilled person will understand that the most common natural amino acids are known by their trivial names and will be aware of the side chain groups present in these amino acids. “Proteinogenic” amino acids are the 22 amino acids that may be naturally encoded or naturally found in the genetic code of organisms. Both the D- and L-stereoisomers of the 22 amino acids are included within this term. “Non-proteinogenic” amino acids are those not naturally encoded or found in the genetic code of any organism. The set of non-proteinogenic amino acids is generally considered to include all organic compounds with an amine (-NH₂) and a carboxylic acid (-COOH) functional group linked via a single additional carbon atom, as well as a side chain and a hydrogen bound to that single additional carbon atom, but excluding selenocysteine, pyrrolysine and the 20 standard amino acids that are incorporated into proteins during translation. Non-proteinogenic amino acids include those amino acids that are intermediates in biosynthesis, those that are post-translationally formed in proteins, and those that possess a physiological role (e.g. components of bacterial cell walls, neurotransmitters and toxins). References to non-polar non-proteinogenic amino acid side chains are references to non-polar side chains (particularly those formed primarily of alkyl and/or aryl groups in the absence of polar groups) which are capable of being bound to an amino acid backbone. References to polar non-proteinogenic amino acid side chains are references to polar side chains (particularly those comprising a hydroxyl, amine, guanidinyl or amide functional group) which are capable of being bound to an amino acid backbone. Unless otherwise stated, the configuration of proteinogenic and non-proteinogenic amino acids includes both D- and L-configurations. In the case of a discrepancy between the names and structures of any of the compounds disclosed herein, the structures provided should prevail. When the stereochemistry of a chiral centre is not explicitly defined herein (i.e. by the use of wedged/hashed bonds) it should be understood that the stereocentre may be present in the R- or S-configuration, or a mixture of both configurations. The R⁵ structural feature represents a linking group which forms a bridge between two separate portions of the molecule. Such linking groups include -SCH₂-. For -SCH₂-, the left-hand hyphen in such linking groups represents the point of attachment to Z, and the right-hand hyphen in such linking groups represents the point of attachment to the carbon atom bound to R⁴. Each pair of adjacent AA¹ AA², AA³ and AA⁴ groups may be linked together via an amide bond between the C1 (carbon number one) of one amino acid with the nitrogen attached to the alpha carbon in the adjacent amino acid, as in a so-called eupeptide bond. Alternatively, one or more adjacent pairs of AA¹ AA², AA³ and AA⁴ may be linked via an isopeptide bond; that is, the side chain of at least one of these amino acids may form part of the backbone of the polypeptide chain. For example, a serine residue (e.g. at the AA⁴ position) may link to the carboxyl group of an adjacent amino acid (e.g. at the AA³ position) via the oxygen atom in the HO-CH₂- side chain of serine, thereby forming an O-acyl linkage between AA³ and AA⁴. Other isopeptide bonding modes known to the skilled person may also be included in the compounds of the invention, e.g. via the oxygen atom of the threonine side chain. The incorporation of isopeptide bonds may be advantageous for one or more properties of the compound of the invention as, for example, it may improve the solubility of the compound. Isopeptide bonds are also capable of being converted into eupeptide bonds under suitable conditions. For example, the isopeptide bond between the serine and lysine groups in Analogue 117 (as described elsewhere herein) may convert into the eupeptide bond, thus forming Analogue 39, under physiological conditions, e.g. at pH 7.4. In one embodiment, adjacent groups in the AA¹ to AA⁴ chain are linked via eupeptide and/or O-acyl isopeptide bonds. In a further embodiment, adjacent groups in the AA¹ to AA⁴ chain are linked solely with eupeptide bonds. Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated. Unless otherwise specified, alkyl and alkoxy groups may also be substituted with one or more halo, and especially fluoro, atoms. Unless otherwise specified, alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated. Unless otherwise specified, alkylene groups may also be substituted with one or more halo atoms. The term “aryl”, when used herein, includes C_6-12 aryl groups such as phenyl, naphthyl, biphenyl and the like. When substituted, aryl groups are preferably substituted with between one and three substituents. The term “heteroaryl”, when used herein, includes C_6-12 heteroaryl groups wherein one, two or three of the ring atoms are selected from nitrogen, oxygen or sulphur, such as pyridyl, indole and the like. The term “acyl” as used herein refers to alkyl groups having a carbonyl group attached to the carbon which forms the point of attachment to the rest of the molecule. The skilled person will realise that all references herein to particular aspects of the invention include references to all embodiments and combinations of one or more embodiments that make up that aspect of the invention. Thus, all embodiments of particular aspects of the inventions may be combined with one or more other embodiments of that aspect of the invention to form further embodiments without departing from the teaching of the invention. In one embodiment of the invention, R⁵ represents -C(O)-. In another embodiment of the invention, Z represents -S- and R⁵ represent -SCH₂-. In another embodiment of the invention, R⁴ represents a proteinogenic or non- proteinogenic amino acid side chain in which the non-proteinogenic amino acid side chain is selected from the group consisting of C_3-6 cycloalkyl, -C(O)OH, -C(O)NH₂ or optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R⁴ may be selected from the list consisting of C_3-6 cycloalkyl, phenyl and biphenyl (e.g. C_3-6 cycloalkyl and biphenyl). In one embodiment, R⁴ is a proteinogenic amino acid side chain that is not a hydrogen (i.e. H) atom or R⁴ is a non-proteinogenic amino acid side chain in which the non- proteinogenic amino acid side chain is selected from the group consisting of C_3-6 cycloalkyl, -C(O)OH, -C(O)NH₂ or optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R⁴ may be selected from the list consisting of C_3-6 cycloalkyl, phenyl and biphenyl (e.g. C_3-6 cycloalkyl and biphenyl). In another embodiment, R⁴ does not represent -C(O)OH or -C(O)NH₂, i.e. R⁴ represents a proteinogenic amino acid side chain or a non-proteinogenic amino acid side chain selected from the group consisting of C_3-6 cycloalkyl or optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R⁴ may be selected from the list consisting of C_3-6 cycloalkyl, phenyl and biphenyl (e.g. C_3-6 cycloalkyl and biphenyl). In a preferred embodiment, R⁴ represents an amino acid side chain selected from the group consisting of serine, methionine, valine and, particularly, leucine, alanine, cyclohexylglycine, cyclohexylalanine, norleucine, norvaline, phenylalanine, biphenylalanine and isoleucine. R^1a may represent H or C_1-4 alkyl (e.g. methyl). In a preferred embodiment, R^1a is selected from the group consisting of H and methyl. R¹ may represent H, C_1-4 alkyl, benzoyl, -C(O)C_1-8 alkyl or -C(O)OC_1-8 alkyl, wherein the latter four groups are optionally substituted by one or more substituents selected from the group consisting of halogen (especially fluoro or chloro atoms) and -NH₂, and AA¹ represents a proteinogenic or non-proteinogenic amino acid. In some embodiments, R¹ represents H, C_1-4 alkyl, benzoyl or -C(O)C_1-8 alkyl, wherein the latter three groups are optionally substituted by -NH₂, and R^1a represents H. R¹ may represent H, C_1-4 alkyl, benzoyl or -C(O)C_1-8 alkyl, wherein the latter three groups are optionally substituted by -NH₂, and AA¹ represents a proteinogenic or non- proteinogenic amino acid. In another embodiment, R¹, R^1a and AA¹ together represent a -C(O)C_1-8 alkyl group in which the C_1-8 alkyl portion is optionally substituted by one or more substituents selected from -NH₂ and phenyl. In a particular embodiment, AA¹ represents an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain, C_3-6 cycloalkyl and optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in AA¹ may be selected from the list consisting of C_3-6 cycloalkyl, heteroaryl, biphenyl and C₆-C₁₀ aryl (optionally substituted by -NH₂ or Q-C(O)NH-). In said embodiments, Q represents heteroaryl, phenyl, biphenyl, naphthyl, C_1-10 alkyl, or C_1-8 alkyl-NH₂, optionally wherein each group (e.g. said phenyl and C1-10 alkyl groups) is substituted by one or more substituents selected from the group consisting of halogen, methyl, methoxy, hydroxybenzamide and phenyl. In other embodiments, Q represents phenyl, biphenyl, naphthyl, C_1-10 alkyl, or C_1-8 alkyl-NH₂, optionally wherein each group (e.g. said phenyl and C_1-10 alkyl groups) is substituted by one or more substituents selected from the group consisting of halogen, methoxy and phenyl. Alternatively, R¹, R^1a and AA¹ together represent a -C(O)C_1-8 alkyl-NH₂ group in which the C_1-8 alkyl portion is optionally substituted by phenyl. In one embodiment, the _{fragment of the compound of formula I may be} represented by the following formula _{wherein S. C.1 represents the side chain of a proteinogenic or non-} proteinogenic amino acid in accordance with the definition of AA¹ above, including all preferences thereof, and R¹ and R^1a are as defined herein. In embodiments where R^1a is hydrogen, the _{fragment of the compound of} formula IA may be represented by the following formula wherein S. C.1 represents the side chain of a proteinogenic or non- proteinogenic amino acid in accordance with the definition of AA¹ above, including all preferences thereof, and R¹ is as defined herein, preferably wherein R¹ represents H, C_1-4 alkyl, benzoyl or -C(O)C_1-8 alkyl, wherein the latter three groups are optionally substituted by -NH₂. Similarly, in other embodiments, the fragment of the compound of formula IA may be represented by the following formula wherein S. C.1 represents the side chain of a proteinogenic or non- proteinogenic amino acid in accordance with the definition of AA¹ above, including all preferences thereof, and R¹ is as defined herein, preferably wherein R¹ represents H, C_1-4 alkyl, benzoyl or -C(O)C_1-8 alkyl, wherein the latter three groups are optionally substituted by -NH₂. In one embodiment, for example when AA¹ is as defined according to any of the embodiments or preferences elsewhere herein, AA¹ is not L-phenylalanine (e.g. not phenylalanine). AA² may represent an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain, C_3-6 cycloalkyl and optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in AA² may be selected from the list consisting of C_3-6 cycloalkyl, C₆-C₁₀ aryl, C₆-C₁₀ arylamine and biphenyl. In a particular embodiment, AA² represents an amino acid residue selected from the list consisting of leucine, tryptophan, cyclohexylalanine, cyclohexylglycine, phenylalanine, tyrosine, allo-isoleucine, alanine, lysine, biphenylalanine, norvaline, norleucine, arginine, naphthylalanine and aminophenylalanine. AA³ may represent an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain and optionally substituted C_1-6 alkyl. Said optional substituents on a C_1-6 alkyl in AA³ may be selected from the list consisting of -NH₂, -NH-C_1-4 alky, -N(C_1-4 alkyl)2, -NH-C(NH)-NH₂, -OH, -C(O)OH, -NHC(O)C_1-8 alkyl and -NHC(O)OC_1-8 alkyl, wherein the latter two groups are optionally substituted by one or more halo, and especially fluoro or chloro, atoms. In a preferred embodiment, AA³ represents an alpha-amino acid bearing a side chain containing at least one -NH₂, -NH-C_1-4 alkyl, -N(C_1-4 alkyl)₂, -NH-C(NH)-NH₂, -NHC(O)C_1-8 alkyl or -NHC(O)OC_1-8 alkyl group (e.g. lysine, arginine, homoarginine, ornithine, 2,4- diaminobutyric acid, and 2,3-diaminopropionic acid). AA³ may represent an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain and optionally substituted C_1-6 alkyl. Said optional substituents on a C_1-6 alkyl in AA³ may be selected from the list consisting of -NH₂, -NH-C(NH)-NH₂, -OH, and -C(O)OH. In a preferred embodiment, AA³ represents an alpha-amino acid bearing a side chain containing at least one -NH₂ group (e.g. lysine, arginine, homoarginine, ornithine, 2,4-diaminobutyric acid, and 2,3- diaminopropionic acid), optionally wherein that -NH₂ group has been alkylated (e.g. mono- or di-alkylated) or acylated. It has been found that such compounds comprising a side-chain with at least one -NH₂ group at AA³ (either as -NH₂ or in an alkylated (e.g. mono- or di-alkylated) or acylated form) display potent antibacterial efficacy. In another embodiment, AA³ represents an amino acid residue selected from the list consisting of lysine, arginine, diaminobutyric acid, diaminopropionic acid, ornithine, homoarginine and alanine. In a preferred embodiment, for example when AA³ is as defined according to any of the embodiments or preferences elsewhere herein, AA³ is not D-lysine (e.g. not lysine). AA⁴ may represent an alpha-amino acid bearing a side chain consisting of an optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in AA⁴ may be selected from the list consisting of -OH, -NH₂ and -SH. Such compounds have been surprisingly found to be particularly effective in inhibiting or killing bacteria. In contrast, compounds in which AA⁴ bears a non-polar side chain (such as Analogue 25 as described in the Examples) have been found to have poorer efficacy in inhibiting and killing bacteria. Other optional substituents on the C_1-6 alkyl group in AA⁴ may be selected from the list consisting of -OR^AA4, -NH-R^AA4, -N(R^AA4)₂, and -SR^AA4, wherein each R^AA4 group independently represents a phenyl group, a -C_1-4 alkyl group or a -C(O)-C_1-4 alkyl group. In a preferred embodiment, AA⁴ represents an amino acid residue selected from the list consisting of ornithine, 2,4-diaminobutyric acid, 2,3- diaminopropionic acid, and particularly serine, cysteine, lysine and threonine. In one embodiment, AA² represents a leucine residue, AA³ represents a lysine residue and AA⁴ represents a serine residue. In a preferred embodiment, AA² represents a D- leucine residue, AA³ represents a D-lysine residue and AA⁴ represents an L-serine residue. R² may represent a non-polar side chain, i.e. a non-polar proteinogenic or non-polar non-proteinogenic amino acid side chain. Compounds of formula I (e.g. compounds of formula IA) in which the R² group is a non-polar side chain (including either a non- polar proteinogenic or non-polar non-proteinogenic amino acid side chain) have been found to be surprisingly effective in inhibiting or killing bacteria. Thus, in a preferred embodiment, R² is a non-polar amino acid side chain. In another embodiment, R² represents a group selected from the list consisting of a non-polar proteinogenic amino acid side chain, C_3-6 cycloalkyl and optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R² may be selected from one or more C_3-6 cycloalkyl groups. In a further embodiment, R² represents an amino acid side chain selected from the list consisting of leucine, isoleucine, valine and, particularly, alanine, lysine, norleucine, norvaline, cyclohexylalanine, cyclohexylglycine and phenylalanine. R³ may represent a group selected from the list consisting of a methionine side chain, a glutamic acid side chain, a valine side chain, a proline side chain, a glutamine side chain, a histidine side chain, an arginine side chain, a serine side chain, a threonine side chain, an asparagine side chain and, particularly, a lysine side chain, a tyrosine side chain, a tryptophan side chain, a cysteine side chain, a non-polar proteinogenic amino acid side chain, a C_3-6 cycloalkyl and an optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R³ may be selected from one or more substituents selected from C_3-6 cycloalkyl, -SH and -SMe groups. It has also been found that structural variation is well tolerated at R³ with good antibacterial efficacy being found for a range of different structures at this position. It has also been found that compounds comprising a non-polar amino acid side chain at R³ or an amino acid side chain containing an amine group or a heteroaryl group at R³ display potent antibacterial efficacy. In a particular embodiment, R³ represents a group selected from the list consisting of a non-polar proteinogenic amino acid side chain, a C_3-6 cycloalkyl and an optionally substituted C_1-6 alkyl. Said optional substituents on the C_1-6 alkyl group in R³ are selected from one or more substituents selected from C_3-6 cycloalkyl, -SH and -Sme groups. In another particular embodiment, R³ represents an amino acid side chain selected from the list consisting of valine, serine, threonine, and particularly, leucine, isoleucine, alanine, lysine, cyclohexylglycine, cyclohexylalanine, phenylalanine, norvaline, norleucine, tyrosine, tryptophan, cysteine and methionine. Novo29’s unusual structure comprises a mixture of L- and D-amino acid residues, along with an asparagine residue. The manufacture of Novo29 is difficult and expensive, in part due to the presence of the asparagine residue. Asparagine synthesis is a complex multi-step process that, for example, frequently proceeds via beta-hydroxy aspartic acid while beta-hydroxy aspartic acid itself requires a six-step synthetic route (see A. Guzmán-Martinez et al., Synlett. 2007 June 1; 2007(10): 1513–1516, and L. Liu et al., Chinese Chemical Letters 29 (2018) 1113–1115). The inventors have surprisingly found that compounds of formula I (e.g. compounds of formula IA) are effective antibacterial agents in spite of the fact that R⁶ is not an amide-containing group. Instead, in the compounds of the invention, R⁶ represents hydrogen or C_1-4 alkyl. This allows for the synthesis to be greatly simplified, particularly where R⁶ forms part of a proteinogenic amino acid residue such as threonine. For this reason, compounds of formula I (e.g. compounds of formula IA) in which R⁶ represents hydrogen or a methyl group are particularly notable. For a similar reason, compounds of the invention in which R⁶ represents hydrogen, Z represents -S-, R⁵ represent -SCH₂- and R⁴ represents -C(O)OH comprise adjacent cysteine residues in the macrocyclic ring portion of the molecule. As these are proteinogenic amino acids, the manufacture of these compounds is cheaper and more efficient than Novo29 which contains an asparagine residue in the macrocyclic ring portion of the molecule. In one embodiment of the invention, Z represents -O- or -NH-. In a preferred embodiment, Z represents -O-. In a preferred embodiment, there is provided a compound of formula I, wherein: R¹ may represent H, benzoyl, methyl, trifluoracetyl, trichloroacetyl, ethoxycarbonyl or (hexyl)oxycarbonyl; R^1a may represent H or methyl; AA¹ may represent 4-(4-pyridinamido)-L-phenylalanine, 4-(2-pyridinamido)-L- phenylalanine, 4-(N-methylimidazol-2-ylamido)-L-phenylalanine, 4-(hex-5-ynamido)- L-phenylalanine, 4-decanamido-L-phenylalanine, 4-(9-(2- hydroxybenzamido)nonanamido)-L-phenylalanine, L-biphenylalanine, L- phenylalanine, 2-naphthyl-L-alanine, 2-naphthamide-L-phenylalanine, 4-benzamido- L-phenylalanine, 4-chloro-benzamido-L-phenylalanine, 4-fluoro-benzamido-L- phenylalanine, 4-methoxy-benzamido-L-phenylalanine, 4-(3,3,3-trifluoro-2-methoxy- 2-phenyl-propanamido)-L-phenylalanine, 4-methylnonanamido-4-L-phenylalanine, 4- methyloctanamido-4-L-phenylalanine or hexanamido-4-L-phenylalanine; or R¹ and AA¹ together represent 4-methyloctanoyl, 4-amino-3-phenyl-butanoyl or 8- aminooctanoyl; AA² may represent D-leucine or D-cyclohexylalanine; AA³ may represent D-lysine, D-arginine, D-homoarginine, Nİ-methyl-D-lysine, Nİ^Nİ- dimethyl-D-lysine, Nİ-trifluoroacetyl-D-lysine, Nİ-trichloroacetyl-D-lysine, Nİ- ethoxycarbonyl-D-lysine, Nİ-(hexyloxy)carbonyl-D-lysine; AA⁴ may represent L-serine; R² may represent a side chain of L-alanine; R³ may represent a side chain of L-leucine, L-cyclohexylglycine, L-cyclohexylalanine, L-norvaline, L-norleucine, L-tyrosine, L-tryptophan or L-phenylalanine, methionine, cysteine; R⁴ may represent a side chain of L-serine, L-methionine, L-valine, L-leucine, L- isoleucine, L-cyclohexylglycine, L-cyclohexylalanine or -C(O)OH; R⁵ may represent -C(O)- or -SCH₂-; R⁶ may represent H or methyl; and/or Z may represent -O-, -NH- or -S-. In a preferred embodiment, there is provided a compound of formula I, wherein: R¹ may represent H or benzoyl; AA¹ may represent L-biphenylalanine, L-phenylalanine, 2-naphthyl-L-alanine, 2- naphthamide-L-phenylalanine, 4-benzamido-L-phenylalanine, 4-chloro-benzamido-L- phenylalanine, 4-fluoro-benzamido-L-phenylalanine, 4-methoxy-benzamido-L- phenylalanine, 4-(3,3,3-trifluoro-2-methoxy-2-phenyl-propanamido)-L-phenylalanine, 4-methylnonanamido-4-L-phenylalanine, 4-methyloctanamido-4-L-phenylalanine or hexanamido-4-L-phenylalanine; or R¹ and AA¹ together represent 4-amino-3-phenyl-butanoyl or 8-aminooctanoyl; AA² may represent D-leucine or D-cyclohexylalanine; AA³ may represent D-lysine, D-arginine or D-homoarginine; AA⁴ may represent L-serine; R² may represent a side chain of L-alanine; R³ may represent a side chain of L-leucine, L-cyclohexylglycine, L-cyclohexylalanine, L-norvaline, L-norleucine, L-tyrosine, L-tryptophan or L-phenylalanine, methionine, cysteine; R⁴ may represent a side chain of L-leucine, L-isoleucine, L-cyclohexylglycine, L- cyclohexylalanine or -C(O)OH; R⁵ may represent -C(O)- or -SCH₂-; R⁶ may represent H or methyl; and/or Z may represent -O-, -NH- or -S-. In another embodiment, there is provided a compound of formula I, wherein: AA¹ may represent a proteinogenic or non-proteinogenic amino acid that is not phenylalanine; AA³ may represent a proteinogenic or non-proteinogenic amino acid that is not lysine; R⁶ may represent hydrogen or a methyl group; and/or Z may represent -O-. In one embodiment, the compound of formula I is not or The group at R², R³ and R⁴ may be attached in either the D- or L-configuration. It is preferred that each of these group is attached in the L-configuration. Thus, for example, when R² represents a methyl group (i.e. the side chain of alanine), the chiral carbon to which R² is bound is preferably in the S-configuration (thus corresponding to L-alanine). In one embodiment, R⁶ preferably represents hydrogen or a methyl group so as to form part of a serine, threonine, diaminopropanoic acid, methyl diaminopropanoic acid or cysteine residue, etc. When R⁶ is not hydrogen (e.g. when R⁶ is methyl), the chiral centre to which R⁶ is bound may be in either the R- or S- configuration, and it has been found that inversion of the chirality at this position is tolerated (i.e. the compounds remain active as antibacterials). However, in particular embodiments, the chiral centre to which R⁶ is bound is in the S-configuration (for example, as is found in a D-threonine residue). In the compounds of the invention, the carbon atom in the macrocyclic ring portion to which R¹-AA¹-AA²-AA³-AA⁴-N(H)- is attached is chiral. This carbon atom is referred to herein as the “linker carbon”. The linker carbon may, together with the neighbouring atoms be considered to be an amino acid residue, such as D-threonine in the case of Analogue 2 (as defined in the Examples). That amino acid residue may be in either the D- or L-configuration. That is, the chiral linker carbon may be in the R- or S- configuration. It has been found that inversion of the chirality at the linker carbon is tolerated, and that compounds remain active as antibacterials when the chirality is inverted. However, in particular embodiments, the amino acid residue bearing the linker carbon is in the D-configuration (i.e. it is in the R-configuration when Z is -O- or -NH-). The amino acid at AA¹, AA², AA³ and AA⁴ may be present in either the D- or L- configuration. It is preferred that AA¹ and AA⁴ are present in the L-configuration while AA² and AA³ are in the D-configuration. Thus, for example, when AA¹ represents phenylalanine, the chiral carbon to which the benzyl side chain is bound is preferably in the S-configuration (thus corresponding to L-leucine). Particular compounds of the invention include those in which: AA¹ is in the L-configuration; AA² is in the D-configuration; AA³ is in the D-configuration; AA⁴ is in the L-configuration; R² is attached in the L-configuration; R³ is attached in the L-configuration; R⁴ is attached in the L-configuration; the chiral centre to which R⁶ is bound is in the S-configuration; and/or the amino acid residue bearing the linker carbon is in the D-configuration. Nevertheless, compounds of the invention have also been particularly found to be tolerant to inversion of the stereochemistry at the chiral centres to which R³ and R⁶ are bound as well as at the linker carbon. Thus, it is preferred that both R³ and R⁶ may be attached in either the D- or L-configuration, and the amino acid residue bearing the linker carbon is in the D- or L-configuration. It has also been found that structural variation is tolerated to a much greater extent at positions represented by AA¹, AA², R³ and R⁴. Thus, in a preferred embodiment, AA³ represents an isoleucine residue (e.g. D-isoleucine), AA⁴ represents a serine residue (e.g. L-serine), R² represents an alanine side chain (e.g. methyl in the L-configuration, and R⁶ represents a hydrogen or methyl group, whereas AA¹, AA², R³ and R⁴ may be varied as described herein. Unless otherwise stated, terms such as “binding”, “bound”, etc., refer to the interaction between molecules or chemical structures which serve to hold those molecules or chemical structures in close proximity to one another. In the context of the present invention, the term “binding”, unless otherwise stated, particularly refers to the binding that occurs as a result of interactions between permanent dipoles or more preferably as a result of hydrogen bonding between the molecular structures involved. In a further embodiment, the compound of the invention is selected from the group consisting of analogues 1–116 as disclosed herein. Preparation The compounds of the invention may be prepared in accordance with techniques known to those skilled in the art, for example as described hereinafter. Thus, according to a second aspect of the invention there is provided a process for the preparation of a compound of formula I, which comprises: (i) deprotection of a compound of formula I in which one or more primary amine groups is protected with a carbamate protecting group, such as by using Boc, CBz or Fmoc, which deprotection may be performed using suitable conditions reagents, such as in the presence of an acid (such as trifluoroacetic acid, hydrochloric acid or p-toluenesulphonic acid) for a Boc protecting group or in the presence of a base (such as piperidine) for an Fmoc protecting group, for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF)); (ii) deprotection of a compound of formula I in which one or more hydroxyl groups is protected with an ether protecting group (such as a tert-butyl, benzyl, allyl, or methoxymethyl ether, preferably a tert-butyl ether), which deprotection may be performed in the presence of an acid (such as trifluoroacetic acid, hydrochloric acid or p-toluenesulphonic acid), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF)); (iii) deprotection of a compound of formula I in which one or more primary amide groups is protected with a trityl-based group (e.g. a dimethoxy trityl group, a monomethoxy trityl group or an unsubstituted trityl group), which deprotection may be performed in the presence of an acid (such as trifluoroacetic acid, hydrochloric acid or p-toluenesulphonic acid), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF)); (iv) deprotection of a compound of formula I in which one or more guanidinyl groups is protected with a sulphonamide protecting group (e.g. 2,2,4,6,7- pentamethyldihydrobenzofuran-5-sulphonyl (Pbf) group), which deprotection may be performed in the presence of an acid (such as trifluoroacetic acid, hydrochloric acid or p-toluenesulphonic acid), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF)); in a particularly preferred embodiment the deprotections of steps (ii), (iii) and (iv) are performed in the presence of trifluoroacetic acid, triisopropylsilane and water; optionally the deprotections of steps (ii), (iii) and (iv) are performed on a solid support and/or in combination with cleavage of the amino acid sequence from the solid support; (v) for compounds in which R^1a is hydrogen, reaction of a compound of formula II, wherein AA² to AA⁴ and R² to R⁴ are as defined hereinabove and are optionally protected; and Z, R⁵ and R⁶ are as defined hereinabove, in a process comprising the steps of: a) reacting the compound of formula II with a compound of formula III, wherein R¹ is as defined hereinabove, R^AA1 is the side chain of the desired AA¹ amino acid (optionally in protected form), and PG¹ represents an optional suitable protecting group (such as a carbamate protecting group, including Boc, CBz or preferably Fmoc), with a suitable peptide coupling reagent; (such as a uronium coupling reagent (for example HATU and TBTU); a benzotriazole coupling reagent (for example HOBt or HOAt), a carbodiimide coupling reagent (for example EDCI, DIC or DCC) or an (imino)cyanoacetate coupling reagent (for example ethyl (hydroxyimino)cyanoacetate (Oxyma)) or combinations thereof), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF) and a suitable base (e.g. trimethylamine, triisopropylethylamine or pyridine), at a temperature of e.g. between room temperature and 50 °C); followed by b) removal of the protecting group PG¹ if present, which may be performed under acidic or basic conditions as appropriate, (e.g. in the presence of piperidine); or (vi) reaction of a compound of formula II, (II) wherein AA² to AA⁴ and R² to R⁴ are as defined in Claim 1 and are optionally protected; and Z, R⁵ and R⁶ are as defined in Claim 1, in a process comprising the step of: a) reacting the compound of formula II with a compound of formula IIIA, wherein R¹ and R^1a are as defined in Claim 1, R^AA1 is the side chain of the desired AA¹ amino acid as defined in Claim 1 (optionally in protected form), with a suitable peptide coupling reagent; or (vii) reaction of a compound of formula IV, wherein AA¹ to AA⁴ and R^1a and R¹ to R⁴ are as defined hereinabove and are optionally protected, and Z, R⁵ and R⁶ are as hereinabove defined, with a suitable peptide coupling reagent (such as a uronium coupling reagent (for example HATU and TBTU); a benzotriazole coupling reagent (for example HOBt or HOAt), a carbodiimide coupling reagent (for example EDCI, DIC or DCC) or an (imino)cyanoacetate coupling reagent (for example ethyl (hydroxyimino)cyanoacetate (Oxyma)) or combinations thereof), under conditions described above. The processes described in steps (i) to (vi) are referred to hereinafter as “the processes of the invention”. In particular embodiments of the second aspect of the invention there is provided a process for the preparation of a compound of formula IA, which process any of (i) to (vii) above with a compound wherein R^1a is hydrogen (i.e. H). By “performed on a solid support” we mean that part or all of the relevant processes are carried out with the peptide sequence covalently bonded to a solid phase resin (for example a chlorotrityl chloride, polysterene or polyethylene glycol resin (e.g. a ChemMatrix ® resin)). The point of attachment to the solid phase resin may be at the N-terminus or, preferably at the C-terminus of the peptide sequence or a precursor thereof. The peptide sequence will normally be bound to the resin through either an amide or ester linkage, wherein either the carbonyl portion or amine portion is derived from the C-terminus or N-terminus amino acid residue as appropriate. The skilled person will be able to determine appropriate solid phase resins for use in the processes of the invention and the most appropriate point of attachment of the resin to the peptide sequence for a given process. Suitable resins include the commercially available resins Rink amide resin and 2-chlorotrityl resin, both of which may be attached to the C-terminus of a peptide sequence, via an amide or ester linkage respectively. Cleavage of the peptide sequence from Rink amide resin and 2-chlorotrityl resin can be achieved under acidic conditions. Cleavage from Rink amide resin results in a primary amide group at the C-terminus of a peptide sequence, and cleavage from 2- chlorotrityl resin results in the carboxylic acid group being restored at the C-terminus. In further embodiments of the processes of the invention, any two or more of the deprotections of steps (i), (ii), (iii) and (iv) may be performed concurrently. Protecting groups that may be removed concurrently include alcohol and primary amide protecting groups that can be removed under acidic conditions (for example ether protecting groups (e.g. tert-butyl) and trityl amide protecting groups). These groups may also be removed concurrently with sulphonamide protecting groups (e.g. Pbf) for the protecting of guanidinyl groups, and with cleavage of the peptide sequence, or a precursor thereto, from Rink amide or 2-chlorotrityl resin. With reference to synthetic processes, by “performed concurrently” we mean that the relevant two or more transformations are achieved under a single set of reaction conditions. Other specific transformation steps that may be employed in the synthesis of analogues of formula I include: (a) peptide coupling, which may for example be facilitated by a suitable peptide coupling reagent such as any of the coupling reagents and conditions as described in step (v) as hereinabove; for compounds of the invention that contain one or more isopeptide bonds, amino acid dimers in which the relevant isopeptide bonding mode is already present may be obtained from commercial sources and used as a reagent in a peptide coupling reaction in order to incorporate the isopeptide bonding mode into the molecule; (b) ester formation, which may for example be facilitated by suitable carboxylic acid activating agents (e.g. carbodiimides such as DIC, DCC and EDCI and/or DMAP), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF)); (c) macrocycle formation, including: amide formation, for example the preparation of a compound of formula I by reacting a compound of formula V wherein AA¹ to AA⁴, Z, and R¹ to R⁶ are as defined as in respect of a compound of formula I; for example, under the conditions described for step (v) a) hereinabove; disulphide formation, for example the preparation of a compound VI; AA¹ to AA⁴ and R¹ to R³ are as defined hereinabove and are optionally protected, R⁶ is as hereinabove defined, and X¹ represents -OH or -NH₂. By oxidising a compound of formula VII wherein AA¹ to AA⁴, R¹ to R³, R⁶ and X¹ are as defined for a compound of formula VI; with a suitable oxidising agent, such as oxygen, hydrogen peroxide or 1,3-dibromo- 5,5-dimethylhydantoin (DBDMH), for example under conditions known to a person skilled in the art (such as in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM, DMF, water, DMSO or mixtures thereof)); (d) protection of reactive functional groups, for example hydroxyl groups, primary or secondary amines, guanidines, carboxylic acids and primary or secondary amides, with suitable protecting groups, for example carbamate protecting groups (e.g Boc, CBz, Fmoc or Alloc groups), ether protecting groups (e.g. tert-butyl ethers), trityl amide protecting groups or sulphonamide protecting groups (e.g. Pbf groups); details of suitable protecting groups and methods for their incorporation can be found in P. G. M. Wuts and T. W. Greene Protective Groups in Organic Synthesis, 4^th edition, 2006, Wiley, 2006; (e) deprotection of protected hydroxyl groups, primary or secondary amines, carboxylic acids, guanidines and primary or secondary amides; suitable procedures for the removal (i.e. deprotection) of protecting groups can be found in P. G. M. Wuts and T. W. Greene Protective Groups in Organic Synthesis, 4^th edition, 2006, Wiley, 2006; (f) cleavage of peptide compounds from solid phase resins (such as Rink amide ChemMatrix^® resin and 2-chlorotrityl resin), for example in the presence of a suitable acid. Compounds of the invention may be prepared by methods analogous to those listed above, together with those that are known to those skilled in the art. Compounds of formula I (e.g. compounds of formula IA) may be prepared using processes involving solid (such as solid-phase peptide synthesis SPPS) or solution phase organic synthesis, as appropriate, using conditions that are known to those skilled in the art. Persons skilled in the art will appreciate that, in order to obtain compounds of formula I (e.g. compounds of formula IA) in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis and whether each step should be performed in solution or on solid phase. A recent review of suitable protecting groups for amino acids is provided by Isidro-Llobet et al. Chem. Rev. 2009, 109, 2455–2504. Advantageously, removal of protecting groups and cleavage from solid phase resins should be performed towards the end (preferably as the final step) of a synthetic route in order to maximise the efficiency of a synthetic process. Uses and Pharmaceutical Preparations The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals. Thus, according to a third aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention in combination with a pharmaceutically-acceptable adjuvant, diluent or carrier. Such formulations are referred to hereinafter as the “formulations of the invention”. According to a fourth aspect of the invention, there is provided the compounds of the invention or the formulations of the invention for use in medicine. The use of compounds or formulations of the invention in medicine includes their use as pharmaceuticals (both for human and veterinary use). The compositions of the present invention may also be useful in other fields of industry. For example, the compositions may be useful as plant protection products (i.e. in agriculture), in cosmetic products (e.g. in creams, toothpaste, lotions and ointments), and hygiene and sterilisation procedures (e.g. in scientific laboratories). In this respect, fifth, sixth and seventh aspects of the invention provide, respectively: (a) a compound or formulation of the invention, as hereinbefore defined, for use in treating or preventing a bacterial infection in a subject; (b) use of a compound or formulation of the invention, as hereinbefore defined, in the manufacture of a medicament for treating or preventing a bacterial infection in a subject; (c) a method of treating or preventing a bacterial infection, which method comprises administration of a therapeutically effective amount of a compound or formulation of the invention as hereinbefore defined to a subject in need thereof; (d) use (e.g. ex vivo use) of a compound or formulation of the invention to kill bacteria. When used herein, the terms “bacteria” (and derivatives thereof, such as “bacterial infection”) includes references to organisms (or infections due to organisms) of the following classes and specific types: Gram-positive cocci, such as Staphylococci (e.g. Staph. aureus, Staph. epidermidis, Staph. saprophyticus, Staph. auricularis, Staph. capitis capitis, Staph. c. ureolyticus, Staph. caprae, Staph. cohnii cohnii, Staph. c. urealyticus, Staph. equorum, Staph. gallinarum, Staph. haemolyticus, Staph. hominis hominis, Staph. h. novobiosepticius, Staph. hyicus, Staph. intermedius, Staph. lugdunensis, Staph. pasteuri, Staph. saccharolyticus, Staph. schleiferi schleiferi, Staph. s. coagulans, Staph. sciuri, Staph. simulans, Staph. warneri and Staph. xylosus) and Streptococci (e.g. beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept. pyogenes), microaerophilic, pyogenic streptococci (Streptococcus “milleri”, such as Strept. anginosus, Strept. constellatus constellatus, Strept. constellatus pharyngidis and Strept. intermedius), oral streptococci of the “mitis” (alpha-haemolytic - Streptococcus “viridans”, such as Strept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis), “salivarius” (non-haemolytic, such as Strept. salivarius and Strept. vestibularis) and “mutans” (tooth-surface streptococci, such as Strept. criceti, Strept. mutans, Strept. ratti and Strept. sobrinus) groups, Strept. acidominimus, Strept. bovis, Strept. faecalis, Strept. equinus, Strept. pneumoniae and Strept. suis, or Streptococci alternatively classified as Group A, B, C, D, E, G, L, P, U or V Streptococcus); Gram-negative cocci, such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava and Neisseria weaveri; Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus; Enterobacteriaceae, such as Escherichia coli, Enterobacter (e.g. Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae) Citrobacter (such as Citrob. freundii and Citrob. divernis), Hafnia (e.g. Hafnia alvei), Erwinia (e.g. Erwinia persicinus), Morganella morganii, Salmonella (Salmonella enterica and Salmonella typhi), Shigella (e.g. Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei), Klebsiella (e.g. Klebs. pneumoniae, Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs. granulomatis (Calymmatobacterium granulomatis) and Klebs. rhinoscleromatis), Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia (e.g. Providencia alcalifaciens, Providencia rettgeri and Providencia stuartii), Serratia (e.g. Serratia marcescens and Serratia liquifaciens), and Yersinia (e.g. Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis); Enterococci (e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus solitarius); Helicobacter (e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae); Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffi and A. radioresistens); Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri); Bacteriodes fragilis; Peptococcus (e.g. Peptococcus niger); Peptostreptococcus; Clostridium (e.g. C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C. histolyticum, C. indolis, C. innocuum, C. irregulare, C. leptum, C. limosum, C. malenominatum, C. novyi, C. oroticum, C. paraputrificum, C. piliforme, C. putrefasciens, C. ramosum, C. septicum, C. sordelii, C. sphenoides, C. sporogenes, C. subterminale, C. symbiosum and C. tertium); Mycoplasma (e.g. M. pneumoniae, M. hominis, M. genitalium and M. urealyticum); Mycobacteria (e.g. Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium lentiflavum, Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi and Mycobacterium xenopi); Haemophilus (e.g. Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaemolyticus); Actinobacillus (e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae); Actinomyces (e.g. Actinomyces israelii); Brucella (e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis); Campylobacter (e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter lari and Campylobacter fetus); Listeria monocytogenes; Vibrio (e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus); Erysipelothrix rhusopathiae; Corynebacteriaceae (e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum); Spirochaetaceae, such as Borrelia (e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri, Borrelia persica, Borrelia turicatae and Borrelia venezuelensis) and Treponema (Treponema pallidum ssp. pallidum, Treponema pallidum ssp. endemicum, Treponema pallidum ssp. pertenue and Treponema carateum); Pasteurella (e.g. Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis); Bordetella (e.g. Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum); Nocardiaceae, such as Nocardia (e.g. Nocardia asteroides and Nocardia brasiliensis); Rickettsia (e.g. Ricksettsii or Coxiella burnetii); Legionella (e.g. Legionalla anisa, Legionalla birminghamensis, Legionalla bozemanii, Legionalla cincinnatiensis, Legionalla dumoffii, Legionalla feeleii, Legionalla gormanii, Legionalla hackeliae, Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla longbeachae, Legionalla maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pneumophila, Legionalla sainthelensi, Legionalla tucsonensis and Legionalla wadsworthii); Moraxella catarrhalis; Stenotrophomonas maltophilia; Burkholderia cepacia; Francisella tularensis; Gardnerella (e.g. Gardneralla vaginalis and Gardneralla mobiluncus); Streptobacillus moniliformis; Flavobacteriaceae, such as Capnocytophaga (e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea and Capnocytophaga sputigena); Bartonella (Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana and Bartonella vinsonii arupensis); Leptospira (e.g. Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai and Leptospira weilii); Spirillium (e.g. Spirillum minus); Bacteroides (e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vulgatus); Prevotella (e.g. Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis and Prevotella zoogleoformans); Porphyromonas (e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levii and Porphyromonas macacae); Fusobacterium (e.g. F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F. periodonticum, F. russii, F. ulcerans and F. varium); Chlamydia (e.g. Chlamydia trachomatis); Chlamydophila (e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittaci)); Leuconostoc (e.g. Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides); Gemella (e.g. Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis); and Ureaplasma (e.g. Ureaplasma parvum and Ureaplasma urealyticum). Thus, compounds of the invention may be used to kill any of the above-mentioned bacterial organisms. Particular bacteria that may be mentioned in this respect include: Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus; Staphylococci, such as Staph. aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)), Staph. Epidermidis and Staph. saprophyticus; Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffi and A. radioresistens); Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris); or Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri). Particular bacteria that may be mentioned in this respect include: Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus; Staphylococci, such as Staph. aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)) and Staph. epidermidis; Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffi and A. radioresistens); Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris); or Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri). Particular bacterial infections that may be mentioned in relation to the fifth to seventh aspects of the invention include infections with: Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus; Staphylococci, such as Staph. aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)), Staph. epidermidis and Staph. saprophyticus; Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffi and A. radioresistens); Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris); or Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri). Particular bacterial infections that may be mentioned in relation to the fifth to seventh aspects of the invention include infections with: Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus; Staphylococci, such as Staph. aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)) and Staph. epidermidis; Acinetobacter (e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffi and A. radioresistens); Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris); or Pseudomonas (e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri). The compounds of the invention have shown antibacterial activity against the resistant bacterial pathogen MRSA, and so may be useful in treating or preventing infections from other resistant bacterial pathogens. In a particular embodiment, there is provided a compound or formulation of the invention, as hereinbefore defined, for use in treating or preventing a bacterial infection caused by methicillin-resistant bacteria. The bacterial infection may, for example, be caused by Gram-positive or Gram- negative bacteria. In particular embodiments, the organism is selected from the group consisting of Mycobacteria, Bacillaceae, Staphylococci, Acinetobacter, Enterobacteriaceae, Klebsiella, Proteus and Pseudomonas. The compounds of the present invention are particularly advantageous as they are capable of inhibiting the growth, survival and reproduction of Gram negative bacteria, something which few existing antibacterial agents are able to do effectively. Thus, in particular embodiments of all of the methods disclosed herein, the bacteria are Gram negative bacteria. In this respect, particular conditions that the compounds and formulations of the invention can be used to treat include tuberculosis (e.g. pulmonary tuberculosis, non- pulmonary tuberculosis (such as tuberculosis lymph glands, genito-urinary tuberculosis, tuberculosis of bone and joints, tuberculosis meningitis) and miliary tuberculosis), anthrax, abscesses, acne vulgaris, actinomycosis, bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis, botulism, Buruli ulcer, bone and joint infections, bronchitis (acute or chronic), brucellosis, burn wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffuse panbronchiolitis, diphtheria, dental caries, diseases of the upper respiratory tract, empymea, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, erysipclas, erysipeloid, erythrasma, eye infections, furuncles, Gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhoea, granuloma inguinale, Haverhill fever, infected burns, infections following dental operations, infections in the oral region, infections associated with prostheses, intraabdominal abscesses, Legionnaire’s disease, leprosy, leptospirosis, listeriosis, liver abscesses, Lyme disease, lymphogranuloma venerium, mastitis, mastoiditis, meningitis and infections of the nervous system, mycetoma, nocardiosis (e.g. Madura foot), non-specific urethritis, opthalmia (e.g. opthalmia neonatorum), osteomyelitis, otitis (e.g. otitis externa and otitis media), orchitis, pancreatitis, paronychia, pelveoperitonitis, peritonitis, peritonitis with appendicitis, pharyngitis, phlegmons, pinta, plague, pleural effusion, pneumonia, postoperative wound infections, postoperative gas gangrene, prostatitis, pseudo-membranous colitis, psittacosis, pulmonary emphysema, pyelonephritis, pyoderma (e.g. impetigo), Q fever, rat-bite fever, reticulosis, Ritter’s disease, salmonellosis, salpingitis, septic arthritis, septic infections, septicameia, sinusitis, skin infections (e.g. skin granulomas), syphilis, systemic infections, tonsillitis, toxic shock syndrome, trachoma, tularaemia, typhoid, typhus (e.g. epidemic typhus, murine typhus, scrub typhus and spotted fever), urethritis, wound infections, yaws, aspergillosis, candidiasis (e.g. oropharyngeal candidiasis, vaginal candidiasis or balanitis), cryptococcosis, favus, histoplasmosis, intertrigo, mucormycosis, tinea (e.g. tinea corporis, tinea capitis, tinea cruris, tinea pedis and tinea unguium), onychomycosis, pityriasis versicolor, ringworm and sporotrichosis. Further conditions that may be mentioned in this respect include infections with MSSA, MRSA, Staph. epidermidis, Staph. saprophyticus, Strept. agalactiae, Strept. pyogenes, Escherichia coli, Klebs. pneumoniae, Klebs. oxytoca, Pr. mirabilis, Pr. rettgeri, Pr. vulgaris, Haemophilis influenzae, Enterococcus faecalis or Enterococcus faecium. Further conditions that may be mentioned in this respect include infections with MSSA, MRSA, Staph. epidermidis, Strept. agalactiae, Strept. pyogenes, Escherichia coli, Klebs. pneumoniae, Klebs. oxytoca, Pr. mirabilis, Pr. rettgeri, Pr. vulgaris, Haemophilis influenzae, Enterococcus faecalis or Enterococcus faecium. The compounds and formulations of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compounds and formulations may be administered at varying doses. Suitable daily doses for the compounds and formulations of the invention in therapeutic treatment of humans are in the range of about 1 to about 2000 mg/m². The most effective mode of administration and dosage regimen for the compounds and formulations of the invention depends on several factors, including the particular condition being treated, the extent and localisation of that condition in the patient being treated, as well as the patient’s state of health and their reaction to the compound being administered. Accordingly, the dosages of the compounds and formulations of the invention should be adjusted to suit the individual patient. Methods for determining the appropriate dose for an individual patient will be known to those skilled in the art. Additionally, compounds of the invention may have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more readily synthesised than, or have other useful pharmacological properties over compounds known in the prior art. The use of certain compounds and formulations of the invention in medicine is, to the knowledge of the inventors, novel. In certain embodiments of the invention, the subject of the treatment or prevention methods is a mammal, particularly a human. Figures The following drawing is provided to illustrate various aspects of the present inventive concept and is not intended to limit the scope of the present invention unless specified herein. Figure 1 shows time-kill kinetics of analogue 72 against MRSA 33591 compared with vancomycin. Examples The invention will now be described in more detail by reference to the following non- limiting Examples. MIC testing For MIC testing all peptides were dissolved in DMSO (according to the method of L. L. Ling, et al., Nature 2015, 517, 455–459). Bacteria were grown on Mueller Hinton broth (oxoid). All incubations were at 37°C. Dilutions were carried out using Mueller Hinton. 100 μl of autoclaved Mueller Hinton broth was added to wells 2-12 on a 96-well plate. 200 μl of the peptide was added to well one at a concentration of 512 μg/ml. 100μl of peptide in well one was taken up and pipetted into well two. The mixture was then mixed via pipetting before 100μl was taken up and pipetted into well three. This process was repeated up to well 11. Once peptide was added to well 11 100 μl was taken up and then discarded ensuring the well 12 had no peptide present. Each well was then inoculated with 100μl of bacteria that had been diluted to an OD600nm of 0.1. This was repeated three times. The 96-well plates were then incubated for 24 hours. The MIC was determined to be the lowest concentration at which there was no growth visible. Results are tabulated in the Examples. Materials All amino acids, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), and Diisoproplycarbodiimide were purchased from Fluorochem. The protecting groups for the amino acids are ^tBu for Glu, Boc for Pro, Tyr, Lys, Trp, Pbf for Arg and Trt for Gln unless specified otherwise. Diisopropylethylamine, supplied as extra dry, redistilled, 99.5% pure, was purchased from Sigma Aldrich. Dimethylformamide (DMF) peptide synthesis grade and Trifluoroacetic acid (TFA) was purchased from Rathburn chemicals. Petroleum ether, Diethyl ether, i-PrOH, MeOH (HPLC grade), and Acetonitrile (HPLC grade) were purchased from Fisher Scientific. Water with the Milli-Q grade standard was obtained in-house from an ELGA Purelab Flex system. 2-Chlorotritylchloride resin (manufacturer’s loading: 1.20 mmol/g) was obtained from Fluorochem. Rink amide Chemmatrix resin (manufacturer’s loading = 0.49 mmol/g) was obtained from Biotage. All chemicals were used without further purification. General Procedure for Peptide Synthesis Peptide syntheses were performed using standard Fmoc Solid Phase Peptide Synthesis (SPPS) protocols on a 2-Chlorotritylchloride resin, loading = 1.20 mmol/g or a Rink Amide Chemmatrix Resin, loading = 0.49 mmol/g using a Biotage Initiator + Alstra fully automated microwave peptide synthesizer. All amino acid couplings were performed using 5 eq. Amino Acid with 5 eq. DIC/Oxyma in DMF as a coupling cocktail by irradiating at 70°C for 5 min. Fmoc deprotection was performed using 20% piperidine in DMF. Peptide cleavage was performed using TFA/TIS/H₂O = 95:2.5:2.5 (3 mL/100 mg resin) for 1h. Peptides were precipitated using cold Et₂O (-20°C) by adding approximately 5x volume of the TFA used for cleavage and centrifuging at 7000 rpm at 0°C. All peptides/conjugates were analysed on a Thermo Scientific Dionex Ultimate 3000 RP-HPLC equipped with a Phenomenex Gemini NX C18110 Å (150 x 4.6 mm) column using the following buffer systems: A: 0.1% HCOOH in Milli-Q water. B: MeCN using a flow rate of 1 ml/min. The column was flushed with 100% A for 5 min prior to an injection and was flushed for 5 min with 95% B and 5% A after the run was finished. Peptides were analysed using the following gradient: 95% A for 2 min. 5-95% B in 15 min. 95% B for 5 min. 95% A for 4 min. Peptides and conjugates were purified using the same gradient as mentioned above, on a Thermo Scientific Dionex Ultimate 3000 RP-HPLC with a flow rate of 5 mL/min using a Phenomenex Gemini NX C18110 Å (150 x 10 mm) semi-prep column. Abbreviations AA amino acid Boc butyloxycarbonyl CBz benzyloxycarbonyl CFU Colony forming units DCM dichloromethane DIC N,N’-diisopropylcarbodiimide DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethyl formamide DMSO dimethyl sulphoxide Eq equivalents Fmoc fluorenylmethyloxycarbonyl h hours min minutes HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HPLC high performance liquid chromatography LC liquid chromatography MeCN acetonitrile mQ Milli-Q water (deionised water) MRSA Methicillin-resistant Staphylococcus aureus MS mass spectrometry Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulphonyl PG protecting group SPPS solid-phase peptide synthesis TFA trifluoroacetic acid TIS triisopropylsilane UV ultraviolet Example 1 – Synthesis of Analogue 4 O Synthesis of Compound 4: a. 4 eq. Fmoc-Ala-OH/8 eq. DIPEA in DCM, 3 h. b. 20% piperidine in DMF followed by 3 eq. AllocHN-_D-Thr-OH, 3 eq. HATU/6 eq. DIPEa. c. 10 eq. Fmoc-Leu-OH, 10 eq. DIC, 5 mol% DMAP in DCM, 1 h followed by capping with Ac₂O/DIPEA 10% in DMF, 20% piperidine in DMf. d. 4 eq. Fmoc-Leu-OH, 4 eq. HATU/8 eq. DIPEA in DMF, 1 h followed by 20% piperidine in DMf. e. 10 eq. Trt-Cl, 15% Et₃N in DCM, 1 H. f. [Pd(PPh3)4]⁰ (0.2 eq.) + 24 eq. PhSiH₃ in DCM, 2 x 30min. g. Fmoc/Boc- AA(PG)-OH (AA = amino acid, PG = protecting group), HATU/DIPEA followed by 20% piperidine in DMf. h. TFA:TIS:DCM = 2:5:93, 2 h. i. 1 eq. HATU/10 eq. DIPEA in DMF, 1h. j. TFA:TIS:H₂O = 95:2.5:2.5, 2 h. Step a. Commercially available 2-Chlorotrityl chloride resin (manufacturer’s loading = 1.2 mmol/g, 167 mg resin) was swelled in DCM in a reactor. To this resin was added 4 eq. Fmoc-Ala-OH/8 eq. DIPEA in DCM and the reactor was shaken for 3 h. The loading determined by UV absorption of the piperidine-dibenzofulvene adduct was calculated to be 0.6 mmol/g, (167mg resin, 0.1 mmol). Any unreacted resin was capped with MeOH:DIPEA:DCM = 1:2:7 by shaking for 1 h. Step b. The Fmoc protecting group was deprotected using 20% piperdine in DMF by shaking for 3 min, followed by draining and shaking again with 20% piperidine in DMF for 10 min. AllocHN-D-Thr-OH was then coupled to the resin by adding 3 eq. of the AA, 3 eq. HATU and 6 eq. DIPEA in DMF and shaking for 1.5 h at room temperature. Step c. Esterification was performed using 10 eq. of Fmoc-Leu-OH, 10 eq. DIC and 5 mol% DMAP in DCM and shaking the reaction for 2h. This was followed by capping the unreacted alcohol using 10% Ac₂O/DIPEA in DMF shaking for 30 min and Fmoc was removed using protocol described earlier in step b. Step d. Fmoc-Leu-OH was coupled using 4 eq. of AA, 4 eq. HATU and 8 eq. DIPEA in DMF and shaking for 1 h followed by Fmoc deprotection using 20% piperidine in DMF as described earlier. Step e. The N terminus of Leu was protected using 10 eq. Trt-Cl and 15% Et₃N in DCM and shaking for 1 h. The protection was verified by the Ninhydrin colour test. Step f. The Alloc protecting group of D-Thr was removed using 0.2 eq. [Pd(PPh³)]⁰ and 24 eq. PhSiH₃ in dry DCM under argon for 20 min. This procedure was repeated increasing the time to 45 min and the resin was washed thoroughly with DCM and DMF to remove any Pd stuck to the resin. Step g. All amino acids were coupled using 4 eq. Amino Acid, 4 eq. DIC/Oxyma using a microwave peptide synthesizer. Coupling time was 10 min. Deprotection cycles were performed as described earlier. Step h. The peptide was cleaved from the resin without cleaving off the protecting groups of the amino acid side chains using TFA:TIS:DCM = 2:5:93 and shaking for 1 h. Step i. The solvent was evaporated and the peptide was redissolved in DMF to which 1 eq. HATU and 10 eq. DIPEA were added and the reaction was stirred for 30 min to perform the cyclization. Step j. The side-chain protecting groups were then cleaved off using TFA:TIS:H₂O = 95:2.5:2.5 by stirring for 1 h. The peptide was precipitated using cold Et₂O (-20°C) and centrifuging at 7000 rpm to obtain an off-white solid. This solid was further purified using RP-C18 column and freeze dried to obtain the compound as a white fluffy solid. The identify of all analogues were confirmed by mass analysis. Example 2 – Synthesis of Analogue 40 Synthesis of Analogue 40 was performed using steps identical with or analogous to those in Example 1 for Analogue 4, except where indicated for the following steps: a. 4 eq. of Fmoc-Leu-OH/8 eq. DIPEA, in DCM, 4 h, 20% piperidine in DMf. b. full synthesis was performed using an automated synthesiser (Multipep CEM), Fmoc- AA(PG)-OH (AA = amino acid, PG protecting group), DIC/Oxyma at 50^OC conventional heating. c. Selective deprotection of Alloc was performed using [Pd(PPh₃)₄]0 (0.2 eq.) + 24 eq. PhSiH₃ in DCM, 2 x 30min. d. 4 eq. of Fmoc-Leu-OH/4 eq. HATU/8 eq. DIPEA in DMF, 1 h. e,f. 20% piperidine in DMF 2 x 10min, followed by partial cleave with TFA:TIS:DCM = 2:2:96, 1 h. g,h. 1 eq. HATU/10 eq. DIPEA in DMF, 1 h, followed by full cleave with TFA:TIS:H₂O = 95:2.5:2.5, 2h. Example 3 – Synthesis of Analogues 104a and 104b Synthesis of Compound 104: a. Fmoc-AA(PG)-OH (AA = amino acid, PG = protecting group), DIC/Oxyma microwave couplings, followed by 20% piperidine in Dimethylformamide (DMF). b. TFA:TIS:H₂O = 95:2.5:2.5, 1 h. c. DMSO:Milli-Q water = 1:3 (peptide concentration 1 mM), 12 h. Example 4 – Chemical structures of Analogues 1 to 198 The following compounds have been made, or may be made, using methods analogous to the methods described above for Analogues 4, 40, 104a and 104b. Mass spectrometry data are provided for those compounds that have been synthesised. Additional synthetic steps are described in Examples 4A to 4C.

Example 4A - Methylated analogues Compounds 90, 133, 141 and 143 and similar were synthesised using relevant methylated building blocks. Synthesis of the analogues were performed using steps identical with or analogous to those in Example 1 for Analogue 4. Example 4B - Acylated analogues Compounds 146 and similar were made using standard acylation protocols. For example, an anhydride or acyl chloride in the presence of base was reacted with Analogue 11 or similar in the presence of base to form Analogue 146 as shown below. Example 4C – NHS activation N-hydroxysuccinimide (NHS) was activated with appropriate alcohol and disuccinimidyl carbonate to form the activated NHS ester. This was then added to Analogue 11 (or similar analogues) in the presence of a base to form Analogue 150.

Example 5 - Mass spectrometry data LC-MS data for Analogues 1 to 43 were collected on a Thermofisher instrument with a Thermo Scientific™ ISQ™ EC Single Quadrupole Mass Spectrometer with a flow rate of 0.6 ml/min was used with the following solvent systems: (A): 0.1% HCOOH in H₂O and (B) MeCN. The column was flushed with 95% A for 2 min, then a gradient from 5% to 95% B over 6 min was used, followed by 2 min of flushing with 95% B. Results are shown in Table 1. Table 1 - Mass spectrometry data for Analogues 1 to 46, 49, 54, 59 to 76, 78 to 81, 90, 92 to 98, 100, 108 to 116, 133, 141, 143, and 153 to 198. NT: Not tested. Example 6 – Activity of Analogues and Reference Compound Novo29 against MRSA, E. coli, A. baumannii and Staphylococcus saprophyticus (49493 and 49907) Various Analogues were screened against MRSA ATCC 33591, E. coli, A. baumannii and Staphylococcus saprophyticus (49493 and 49907). The MIC data is given in Table 2. All of the tested analogues showed potent antibacterial activity against MRSA. Most notably, Analogue 39 is 16-32 times more potent than natural Novo29. Table 2 - MIC values MIC: Minimum Inhibitory Concentration. NT: Not tested. ^*MRSA ATCC 33591. ^**E. coli GKCW101 was used for Analogues 1-116; E coli K12 was used for Natural Novo29. *^**Reference Compound as formula (III) in US 2022/185845A1, Table 2, page 18. Example – 7 - Microsomal stability in human and rat Analogue 72 was evaluated for microsomal stability in human and rat liver microsomes. The tested analogue displayed good microsomal stability (see Table 3). Table 3 – Microsomal stability of Analogue 72 in human and rat liver microsomes. Example – 8 - Cytotoxicity Analogue 72 was evaluated in two mammalian cells lines, HepG2 and A549. Analogue 72 displayed no cytotoxicity at 100μM, indicating a favourable safety profile. Example – 9 - Time kill kinetics against MRSA 33591 Analogue 72 showed superior antibacterial activity against MRSA in comparison to clinical antibiotic vancomycin. The results are shown in Figure 1.

Claims

Claims 1. A compound of formula I, or a pharmaceutically-acceptable salt or solvate thereof, wherein: R¹ represents H, C_1-4 alkyl, benzoyl, -C(O)C_1-8 alkyl or -C(O)OC_1-8 alkyl, wherein the latter four groups are optionally substituted by one or more substituents selected from the group consisting of halogen and -NH₂; R^1a represents H or C_1-4 alkyl; AA¹ represents a proteinogenic or non-proteinogenic amino acid; or R¹, R^1a and AA¹ together represent a -C(O)C_1-8 alkyl group in which the C_1-8 alkyl portion is optionally substituted by one or more substituents selected from -NH₂ and phenyl; AA², AA³, and AA⁴ each independently represents a proteinogenic or non-proteinogenic amino acid; R², R³ and R⁴ each independently represents a proteinogenic or non-proteinogenic amino acid side chain; R⁵ represents -C(O)- or -SCH₂-; R⁶ represents hydrogen or C_1-4 alkyl; and Z is -O-, -NH- or -S-.

2. The compound according to Claim 1, wherein R⁵ represents -C(O)-.

3. The compound according to Claim 1 or Claim 2, wherein R⁴ represents a proteinogenic or non-proteinogenic amino acid side chain wherein said non- proteinogenic amino acid side chain is selected from the group consisting of C_1-6 alkyl (optionally substituted with C_3-6 cycloalkyl, phenyl or biphenyl), C_3-6 cycloalkyl, - C(O)OH and -C(O)NH₂.

4. The compound according to Claim 3, wherein said non-proteinogenic amino acid side chain represented by R⁴ is selected from the group consisting of C_1-6 alkyl (optionally substituted with C_3-6 cycloalkyl, phenyl or biphenyl) and C_3-6 cycloalkyl.

5. The compound according to any one of the preceding claims, wherein: (i) AA¹ represents an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain, C_3-6 cycloalkyl and C_1-6 alkyl, wherein said C_1-6 alkyl is optionally substituted by C_3-6 cycloalkyl, heteroaryl, biphenyl or C6-C10 aryl (optionally substituted by -NH₂ or Q-C(O)NH-), and wherein Q represents heteroaryl, phenyl, biphenyl, naphthyl, C_1-10 alkyl, or C_1-8 alkyl- NH₂, optionally wherein each group is substituted by one or more substituents selected from the group consisting of halogen, methyl, methoxy, hydroxybenzamide and phenyl; or (ii) R¹, R^1a and AA¹ together represent a -C(O)C_1-8 alkyl-NH₂ group in which the C_1-8 alkyl portion is optionally substituted by phenyl.

6. The compound according to any one of the preceding claims, wherein AA² represents an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain, C_3-6 cycloalkyl and C_1-6 alkyl optionally substituted by C_3-6 cycloalkyl, C6-C10 aryl, C6-C10 arylamine or biphenyl.

7. The compound according to any one of the preceding claims, wherein AA³ represents an alpha-amino acid bearing a side chain selected from the group consisting of a proteinogenic amino acid side chain and C_1-6 alkyl, wherein said C_1-6 alkyl is optionally substituted by one or more substituents selected from the group consisting of -NH₂, -NH-C_1-4 alkyl, -N(C_1-4 alkyl)2, -NH-C(NH)-NH₂, -OH, -C(O)OH, -NHC(O)C_1-8 alkyl and -NHC(O)OC_1-8 alkyl, wherein the latter two groups are optionally substituted by one or more halo (optionally fluoro or chloro) atoms; optionally wherein the side chain of AA³ contains at least one -NH₂ group.

8. The compound according to any one of the preceding claims, wherein AA⁴ represents an alpha-amino acid bearing a side chain selected from the group consisting of C_1-6 alkyl optionally substituted by one or substituents selected from -OH, -NH₂, -SH, -OR^AA4, -NH-R^AA4, -N(R^AA4)₂, and -SR^AA4, wherein each R^AA4 group independently represents a phenyl group, a -C_1-4 alkyl group or a -C(O)-C_1-4 alkyl group; optionally wherein AA⁴ is an amino acid residue selected from the group consisting of ornithine, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, serine, cysteine, lysine and threonine.

9. The compound according to any one of the preceding claims, wherein R² is selected from the group consisting of a non-polar proteinogenic amino acid side chain, C_1-6 alkyl (optionally substituted by one or more C_3-6 cycloalkyl substituents) or C_3-6 cycloalkyl.

10. The compound according to any one of the preceding claims, wherein R³ is selected from the group consisting of a lysine side chain, a tyrosine side chain, a tryptophan side chain, a cysteine side chain, a non-polar proteinogenic amino acid side chain, C_1-6 alkyl (optionally substituted by one or more substituents selected from C_3-6 cycloalkyl, -SH and -SMe) or C_3-6 cycloalkyl; optionally wherein R³ is selected from the group consisting of a non-polar proteinogenic amino acid side chain, C_1-6 alkyl (optionally substituted by one or more substituents selected from C_3-6 cycloalkyl, -SH and -SMe) or C_3-6 cycloalkyl.

11. The compound according to any one of the preceding claims, wherein R⁶ represents hydrogen or methyl.

12. The compound according to any one of the preceding claims, wherein Z represents -O- or -NH-, optionally wherein Z represents -O-.

13. The compound according to Claim 1, wherein the compound is selected from the group consisting of: and pharmaceutically-acceptable salts and solvates thereof.

14. A pharmaceutical formulation comprising a compound as defined in any one of Claims 1 to 13 in combination with a pharmaceutically-acceptable adjuvant, diluent or carrier.

15. A compound as defined in any one of Claims 1 to 13, or a pharmaceutical formulation as defined in Claim 14, for use in medicine.

16. A compound as defined in any one of Claims 1 to 13, or a pharmaceutical formulation as defined in Claim 14, for use in the treatment or prevention of a bacterial infection in a subject.

17. The compound or pharmaceutical formulation for use according to Claim 16, wherein the bacterial infection is caused by methicillin-resistant bacteria.

18. The compound or pharmaceutical formulation for use according to Claim 16 or Claim 17, wherein the bacterial infection is caused by Gram-positive or Gram-negative bacteria, for example an organism selected from the group consisting of mycobacteria, Bacillaceae, Staphylococci, Acinetobacter, Enterobacteriaceae, Klebsiella, Proteus and Pseudomonas.

19. The compound or pharmaceutical formulation for use according to any one of Claims 16 to 18, wherein the subject is a human.

20. A process for the preparation of a compound of formula I as defined in Claim 1, which process comprises: (i) deprotection of a compound of formula I in which one or more primary amine groups is protected with a carbamate protecting group, in the presence of an acid or a base; (ii) deprotection of a compound of formula I in which one or more hydroxyl groups is protected with an ether protecting group, in the presence of an acid; (iii) deprotection of a compound of formula I in which one or more primary amide groups is protected with a trityl-based group, in the presence of an acid; (iv) deprotection of a compound of formula I in which one or more guanidinyl groups is protected with a sulphonamide protecting group, in the presence of an acid; (v) for compounds in which R^1a is hydrogen, reaction of a compound of formula II, (II) wherein AA² to AA⁴ and R² to R⁴ are as defined in Claim 1 and are optionally protected; and Z, R⁵ and R⁶ are as defined in Claim 1, in a process comprising the steps of: a) reacting the compound of formula II with a compound of formula III, (^III) wherein R¹ is as defined in Claim 1, R^AA1 is the side chain of the desired AA¹ amino acid as defined in Claim 1 (optionally in protected form), and PG¹ represents an optional suitable protecting group, with a suitable peptide coupling reagent; followed by b) removal of the protecting group PG¹ if present; or (vi) reaction of a compound of formula II, (II) wherein AA² to AA⁴ and R² to R⁴ are as defined in Claim 1 and are optionally protected; and Z, R⁵ and R⁶ are as defined in Claim 1, in a process comprising the step of: a) reacting the compound of formula II with a compound of formula IIIA, (^IIIA) wherein R¹ and R^1a are as defined in Claim 1, R^AA1 is the side chain of the desired AA¹ amino acid as defined in Claim 1 (optionally in protected form), with a suitable peptide coupling reagent; or (vii) reaction of a compound of formula IV, (IV) wherein AA¹ to AA⁴ and R^1a and R¹ to R⁴ are as defined in Claim 1 and are optionally protected, and Z, R⁵ and R⁶ are as defined in Claim 1, with a suitable peptide coupling reagent.