Bacterial resistance to antibiotics: Modified target sites

Advanced Drug Delivery Reviews 57 (2005) 1471 – 1485 www.elsevier.com/locate/addr

Bacterial resistance to antibiotics: Modified target sites Peter A. Lambert Pharmaceutical and Biological Sciences, Aston University, Birmingham B4 7ET, United Kingdom Received 22 November 2004; accepted 11 April 2005 Available online 16 June 2005

Abstract Alteration in the target sites of antibiotics is a common mechanism of resistance. Examples of clinical strains showing resistance can be found for every class of antibiotic, regardless of the mechanism of action. Target site changes often result from spontaneous mutation of a bacterial gene on the chromosome and selection in the presence of the antibiotic. Examples include mutations in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In other cases, acquisition of resistance may involve transfer of resistance genes from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Examples of these mechanisms include acquisition of the mecA genes encoding methicillin resistance in Staphylococcus aureus and the various van genes in enterococci encoding resistance to glycopeptides. D 2005 Elsevier B.V. All rights reserved. Keywords: Bacterial resistance; Antibiotics; Modified targets; Resistance genes; Genetic exchange

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Penicillin binding proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. MecA in MRSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Mosaic PBPs in Streptococcus pneumoniae . . . . . . . . . . . . . . . . . . . . . 2.3. Altered PBPs in Neisseria gonorrhoeae . . . . . . . . . . . . . . . . . . . . . . . 2.4. Mosaic PBPs in Neisseria meningitidis . . . . . . . . . . . . . . . . . . . . . . . 2.5. Low affinity PBPs in enterococci . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. h-Lactam resistance associated with PBP changes in other organisms . . . . . . . 2.6.1. Haemophilus influenzae . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Helicobacter pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.3. Proteus mirabilis, Acinetobacter baumanii and Pseudomonas aeruginosa . 2.6.4. Streptococcus pyogenes. . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.5. Listeria monocytogenes . . . . . . . . . . . . . . . . . . . . . . . . . . .

E-mail address: [email protected]. 0169-409X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2005.04.003

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3. 4. 5. 6. 7.

Peptidoglycan: increased amount in the cell wall and altered stem peptides . . . . . . Modification of peptidoglycan precursors . . . . . . . . . . . . . . . . . . . . . . . . DNA gyrase and topoisomerase IV . . . . . . . . . . . . . . . . . . . . . . . . . . . RNA polymerase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ribosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Methylation and mutation of 23S rRNA, mutation of 50S ribosomal proteins . . 7.2. Mutation of 16S rRNA and 30S ribosomal subunit proteins . . . . . . . . . . . 8. Mycolic acid synthesis in Mycobacterium tuberculosis involving katG, inhA and kasA 9. Enoyl reductase encoded by fabI . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Dihydrofolate reductase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Pyrazinamidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Iso-leucyl-tRNA synthetase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. Elongation factor G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Lipopolysaccharide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction A key feature of the target sites for antimicrobial agents is their vital role in microbial growth and survival. Interference with their function is either lethal to the cells or inhibitory to cell growth. For selective antimicrobial action the target must also be absent from mammalian cells or, if present, must differ sufficiently from its mammalian counterpart to allow for selective inhibition of the bacterial target. The peptidoglycan component of the bacterial cell wall provides an excellent example of a selective target. It is essential to the growth and survival of most bacteria and has a chemical structure and composition unlike any mammalian macromolecule. Consequently, enzymes involved in its synthesis and assembly provide excellent targets for selective inhibition. The most important of these are the transpeptidases, targets of the h-lactams, and transglycosylases, substrates of which are the targets of the glycopeptides. Most of the other major classes of antimicrobial agent act at targets that are present in mammalian cells but differ sufficiently to allow for selective inhibition of the bacterial counterparts. These include agents that interfere with protein synthesis (aminoglycosides, tetracyclines, macrolides, chloramphenicol, fusidic acid, mupirocin, streptogramins, oxazolidinones); transcription via RNA polymerase (the rifamycins); chromosome segregation (quinolones) and integrity (metronidazole); and folic acid metabolism (trimethoprim, pyrimethamine).

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Because of the vital cellular functions of the target sites, organisms cannot evade antimicrobial action by dispensing with them entirely. However, it is possible for mutational changes to occur in the target that reduce susceptibility to inhibition whilst retaining cellular function. Mutations that achieve this occur in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In some cases, the modification in target structure needed to produce resistance (that is, interfere with binding of the antimicrobial agent) requires other changes in the cell to compensate for the altered characteristics of the target. This is the case in the most important example of a target change, the acquisition of the altered transpeptidase, MecA in Staphylococcus aureus that results in resistance to methicillin (methicillin-resistant S. aureus, MRSA) and to most other h-lactam antibiotics. To continue to function efficiently in peptidoglycan biosynthesis, MecA needs alterations to be made in the composition and structure of the peptidoglycan, which involves functioning of a number of additional genes.

2. Penicillin binding proteins 2.1. MecA in MRSA MRSA achieves high-level resistance to methicillin and other h-lactam antibiotics through acquisition and expression of the mecA gene [1]. This gene encodes

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penicillin-binding protein 2a (PBP2a, also known as PBP2V). PBP2a belongs to the group of biosynthetic enzymes involved in assembly of the peptidoglycan component of the bacterial cell wall. The mecA gene is carried on a large genetic element called the staphylococcal cassette chromosome mec (SCCmec) that is integrated into the MRSA chromosome near the origin of replication [2]. SCCmec is believed to have been acquired by horizontal transfer from a coagulase-negative staphylococcus species, possibly the animal pathogen, Staphylococcus sciuri. Five different types of SCCmec, designated types I–V, are currently recognised, together with some variants [3]. The different SCCmec types vary in the composition and order of genes encoded in the element and they differ in size from 21 to 67 kb. MRSA isolates can be typed by PCR analysis of SCCmec, providing useful information on the epidemiology of isolates [4]. The interaction between a h-lactam antibiotic and a PBP involves rapid, reversible formation of a noncovalent complex followed by a nucleophilic attack on the h-lactam ring by the side chain oxygen atom of a serine residue at the active site of the enzyme. This forms a relatively stable covalent complex in which the serine is acylated by the hydrolysed h-lactam [5]. Kinetic studies indicate that the reduced sensitivity of PBP2a results from a rate constant for the acylation reaction that is reduced by a factor of 3 orders of magnitude rather than failure to form the initial noncovalent complex [6]. Studies on the kinetics of PBP2a with several h-lactam antibiotics (including penicillins, cephalosporins and a carbapenem) confirm that the rate constant for acylation of the serine is reduced by 3–4 orders of magnitude compared to penicillinsensitive PBP enzymes [7]. However, elevated dissociation constants (K d) for the non-covalent pre-acylation complexes with the h-lactam antibiotics suggest that a combination of reduced non-covalent binding and acylation are responsible for resistance [7]. Comparison of the crystal structures of a soluble derivative of PBP2a in its native (apo) form and the acylated complexes formed by reaction with nitrocefin, penicillin G and methicillin shows that the active site must undergo marked conformational changes to permit acylation of the active site serine [8]. Transition from the initial non-covalent complex to the acylated intermediate requires considerable rearrangement of the enzyme’s structure to bring the h-lactam

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into a position to acylate the active site serine. Such major conformational changes are not necessary for the equivalent reaction to occur in h-lactam-sensitive enzymes that have been studied in this way [9]. A number of h-lactam antibiotics that retain activity against PBP2a have been designed including modified cephalosporins [10–14], carbapenems [15,16] and a trinem [17]. These new agents show activity against MRSA and are in various stages of development. 2.2. Mosaic PBPs in Streptococcus pneumoniae Resistance to h-lactam antibiotics in S. pneumoniae is due to the development of PBPs with decreased affinity for the antibiotics. Resistance to third-generation cephalosporins is due to the presence of altered forms of PBP1a and 2x, whereas penicillin resistance also involves alterations in PBP2b [18–20]. The altered PBPs are generated by recombinational events between the PBP genes of S. pneumoniae and related PBP genes from closely related streptococcal species acquired by transformation of this naturally competent organism [21,22]. 2.3. Altered PBPs in Neisseria gonorrhoeae N. gonorrhoeae has four PBPs, designated PBP 1, 2, 3, and 4 [23]. Of these, only PBP 1 and 2 are essential for cell viability and are, thus, potential antibiotic killing targets in N. gonorrhoeae. Because penicillin G has an approximately 10-fold higher rate of acylation of PBP 2 than of PBP 1, it kills N. gonorrhoeae at its MIC by inactivation of PBP 2. Penicillin-resistant strains of N. gonorrhoeae are capable of transferring their resistance genes to susceptible strains via transformation and homologous recombination. Susceptible strains of N. gonorrhoeae become resistant to penicillin by acquiring multiple resistance genes in a stepwise fashion. Transformation to high-level penicillin resistance is mediated by the penA gene, encoding altered forms of PBP 2 that display 5- to 10-fold decreases in their rate of acylation by penicillin [24]. Mutations in PBP 1 (encoded by the ponA gene) can also contribute to high-level penicillin resistance. A mutation in ponA producing a single amino acid change in PBP 1 has been identified in penicillin-resistant N. gonorrhoeae strains [25]. The altered PBP 1 has a 3- to 4-fold lower rate of

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acylation than wild-type PBP 1 with a variety of hlactam antibiotics. High-level resistance to penicillins involves participation of other genes, including penC and further transformations involving genes encoding efflux systems and altered outer membrane porins in addition to the PBP changes [26]. 2.4. Mosaic PBPs in Neisseria meningitidis The PBP 2 genes (penA) of penicillin-resistant N. meningitidis have a mosaic structure generated by the introduction of segments of the penA genes of related Neisseria species [27] particularly the commensal species Neisseria flavescens and Neisseria cinerea [28,29]. 2.5. Low affinity PBPs in enterococci Enterococci have a low susceptibility to h-lactams that results from the presence of intrinsically lowaffinity PBPs. Five PBPs can be detected in Enterococcus faecalis and six in Enterococcus faecium. Of these, PBPs 3 and 4 of E. faecalis and PBPs 4 and 5 of E. faecium are the relevant target enzymes of the hlactam antibiotics [30]. In E. faecium, highly resistant strains overproduce the low-affinity PBP 5, which, compared with PBP 5 of moderately resistant strains, has reduced penicillin-binding capability [31]. Analysis of PBP 5 variants of clinical isolates with different levels of h-lactam resistance shows that particular combinations of mutations are associated with highlevel resistance [32]. The crystal structure of the acylenzyme complex of E. faecium PBP5 with benzylpenicillin reveals characteristics of the active site that distinguish it from that of other PBPs of known structure [33]. In particular, the peptide loop forming one side of the active site is more rigid than that of sensitive PBPs, and shows similarities in structure to that of the low affinity PBP2a in MRSA strains. The E. faecium PBP 5 active site also contains a hydrophobic valine residue that could reduce accessibility for h-lactams. 2.6. b-Lactam resistance associated with PBP changes in other organisms 2.6.1. Haemophilus influenzae Although resistance to penicillins in H. influenzae is mainly due to h-lactamase production, resistance

in the absence of h-lactamase production has been reported, particularly in Japan [34,35], where multiple mutations were found in the ftsI gene encoding PBP 3. 2.6.2. Helicobacter pylori Amoxicillin-resistant H. pylori are increasing worldwide [36]. Profiles of the three major PBPs of resistant and sensitive strains are generally similar but mutations in pbp1 have been linked to amoxicillin resistance in this organism [37,38]. 2.6.3. Proteus mirabilis, Acinetobacter baumanii and Pseudomonas aeruginosa A decrease in affinity of PBP 2 for imipenem has been reported for a resistant strain P. mirabilis suggesting that imipenem resistance in this organism results from altered PBPs [39]. Similar reports have been made for imipenem resistance in A. baumanii [40] and P. aeruginosa [41] although other factors, including permeability and efflux, are likely to contribute to resistance. 2.6.4. Streptococcus pyogenes Study of five penicillin-tolerant group A streptococci and their isogenic non-tolerant strains, and seven unrelated non-tolerant group A streptococci reveals a number of changes in the PBPs [42]. The most striking change in penicillin-tolerant strains is decreased binding of penicillin to PBP 3 and increased binding to PBP 5, whilst PBP 2a is replaced by a new PBP (PBP 2aV) of lower electrophoretic mobility. These results suggest that changes in PBP 2aV and PBP 5 in combination with other PBP alterations play a role in penicillin tolerance found in group A streptococci. 2.6.5. Listeria monocytogenes PBPs in a strain of L. monocytogenes with decreased susceptibility to imipenem and penicillin G but increased susceptibility to cefotaxime showed a 10-fold decrease in affinity of PBP 3 for penicillin G and imipenem and a 2-fold increase in affinity for cefotaxime compared with a sensitive strain [43]. The results suggest that the alteration of PBP 3 is responsible for the decreased susceptibility to penicillin and imipenem and that PBP 3 might be an essential target of h-lactam antibiotics in L. monocytogenes.

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3. Peptidoglycan: increased amount in the cell wall and altered stem peptides The glycopeptide antibiotics vancomycin and teicoplanin inhibit bacterial cell wall synthesis by binding non-covalently to the peptidyl-d-alanyl-d-alanine (d-Ala-d-Ala) termini of peptidoglycan precursors, blocking their incorporation into the cell wall by transglycosylase action [44]. Vancomycin-resistant S. aureus (VRSA) were first isolated in Japan in 1997 and subsequently in several other countries [45]. The sensitivities of these strains to vancomycin (MIC = 8 Ag/ ml) and the heterogeneous nature of the resistance within populations led to a number of terms being used for them, including hetero-VRSA, vancomycinintermediate S. aureus (VISA) and glycopeptide-intermediate S. aureus (GISA) [46]. When compared with vancomycin-susceptible control strains, they show a number of changes in their cell wall metabolism including a 2-fold increase in cell wall thickness, an increased proportion of peptidoglycan stem peptides containing non-amidated glutamine residues and reduced peptidoglycan cross-linking [47]. These factors are thought to cause the intermediate level of vancomycin resistance through an affinity trapping mechanism [45]. The thicker cell wall with its many binding sites for vancomycin has been shown to trap the antibiotic molecules [47], reducing the number of vancomycin molecules that reach the cytoplasmic membrane where the transglycosylase targets are located.

4. Modification of peptidoglycan precursors The most frequent cause of resistance to the glycopeptide antibiotics in E. faecium and E. faecalis is the acquisition of one of two related gene clusters, termed VanA and VanB. These gene clusters encode enzymes that produce a modified peptidoglycan precursor terminating in d-Alanyl-d-Lactate (d-Ala-dLac) instead of d-Ala-d-Ala [48]. The glycopeptides bind with much lower affinity to d-Ala-d-Lac than to d-Ala-d-Ala [49]. The low affinity binding of glycopeptides to d-Ala-d-Lac results from an altered pattern of intermolecular hydrogen bonding responsible for the normally high affinity binding between antibiotic and substrate. Interaction between the substrate and glycopeptide is a complex cooperative process

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involving dimerisation and conformational changes in the glycopeptide [50–52]. The VanA and VanB clusters comprise three genes (vanHAX and vanH B BX B ) required for resistance and presumed to originate from glycopeptideproducing bacteria. The vanH or vanH B genes encode a dehydrogenase that reduces pyruvate to d-lactate; vanA or vanB encode a ligase that synthesizes d-Ala-d-Lac, and vanX or vanX B encode d,ddipeptidases that hydrolyse pre-existing d-Ala-dAla. Together these enzymes produce peptidoglycan precursors containing d-Ala-d-Lac instead of d-Alad-Ala. Glycopeptide resistance due to expression of the VanA and VanB clusters is induced by the presence of glycopeptide antibiotic, a process that is regulated by the two-component regulatory systems, vanRS and vanR B S B . The gene clusters responsible for VanA and VanB resistance are located on transposable elements, and both transposition and plasmid transfer have resulted in the dissemination of these resistance genes into other species of enterococci. Other rarer forms of acquired resistance gene clusters include VanD in E. faecium [53]; VanE [54] and VanG [55] in E. faecalis. Intrinsic resistance occurs in some enterococcal species, particularly in Enterococcus casseliflavus and Enterococcus gallinarum due to the VanC gene cluster. The first isolation of clinical strains of MRSA expressing high-level resistance to vancomycin (MIC = 32 Ag/ml) through acquisition of the enterococcal VanA gene cluster occurred in 2002 [56,57]. The presence of two different antibiotic resistance mechanisms in the same strain, encoded by SCCmecA in the chromosome and the VanA cluster on a plasmid, results in multiple changes in peptidoglycan composition [58]. The two gene clusters appear to use different sets of enzymes for the assembly of modified peptidoglycan. A number of semi-synthetic glycopeptides that retain activity against VRE and MRSA and exhibit improved pharmacokinetic and pharmacodynamic properties are in the process of evaluation and clinical development [59]. Oritavancin is a derivative of chloroeremomycin (itself an analogue to vancomycin) with activity against VRE, penicillin-resistant S. pneumoniae, MRSA and VISA strains [60]. Telavancin, a vancomycin analogue, and dalbavancin, a derivative of a teicoplanin analogue, have improved adsorption,

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distribution, metabolism and excretion properties [61,62].

5. DNA gyrase and topoisomerase IV Fluoroquinolones act by inhibiting DNA gyrase and topoisomerase IV, two enzymes involved in bacterial DNA synthesis [63]. DNA gyrase introduces negative superhelical twists in the bacterial DNA double helix ahead of the replication fork. It comprises two GyrA and two GyrB subunits, encoded by the gyrA and gyrB genes, respectively. Topoisomerase IV is responsible for decatenation of interlinked daughter chromosomes produced at the end of a round of replication. It comprises two ParC (GrlA in S. aureus) subunits and two ParE (Grl B in S. aureus) subunits encoded by the parC and parE genes, respectively. Both enzymes are needed to aid separation of daughter chromosomes during replication. Fluoroquinolones interact with the complexes formed between DNA and the DNA gyrase or topoisomerase IV enzymes creating conformational changes that result in the inhibition of normal enzyme activity. By binding to the enzyme–DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV. Ternary complexes of drug, enzyme and DNA block progress of the replication fork. Action of fluoroquinolones results from conversion of the topoisomerase–quinolone–DNA complex to an irreversible form and generation of double-strand breaks in DNA by denaturation of the topoisomerase [64]. Resistance to fluoroquinolones can result from chromosomal mutations in both the DNA gyrase and topoisomerase IV target enzymes [65]. Alterations in either the GyrA or GyrB subunits of DNA gyrase occur most commonly in fluoroquinolone-resistant Gram-negative bacteria. Mutations in the GyrA subunit occur in the quinolone resistance-determining region of the gyrA gene encoding the portion of the GyrA subunit that is bound to DNA during enzyme activity. The most common mutations in this region cause resistance through decreased drug affinity for the altered gyrase–DNA complex [66]. GyrB mutations occur less commonly than gyrA mutations. They cluster in an analogous quinolone resistance-determining region domain but their effect on drug binding is not clear. GyrB mutations produce lower levels of

resistance than gyrA mutations [66]. Topoisomerase IV alterations due to mutations in ParC or ParE also occur in Gram-negative bacteria but appear to be of less importance, since fluoroquinolone resistance only results when mutations are also present in the DNA gyrase [66]. In Gram-positive bacteria the situation is reversed, with DNA gyrase serving as a secondary target to topoisomerase IV [67]. Thus, mutations in topoisomerase IV occur more frequently than in DNA gyrase. Topoisomerase IV mutations in fluoroquinolone-resistant Gram-positive bacteria, particularly in S. aureus and S. pneumoniae, occur in either subunit [68,69]. However, mutations in ParC (GrlA in S. aureus) are more common than mutations in ParE (GrlB in S. aureus) and are believed to play a more important role in resistance [70]. The ParC subunit has an analogous quinolone resistance-determining region domain and resistance is thought to be due to reduced drug affinity [66]. New experimental quinolones produced to overcome resistance problems include DK507k [71] and WCK 771 [72,73]. These agents retain effective inhibitory activity against penicillin-resistant S. pneumoniae and MRSA despite mutations in the targets and the action of efflux pumps.

6. RNA polymerase Rifampicin is an important drug in the treatment of TB [74]. Because of the rapid development of resistance, rifampicin has limited use in monotherapy but in combination therapy with a variety of antimicrobials, it has many applications for treatment of serious Gram-positive and Gram-negative infections [75]. Its target site is the h-subunit of RNA-polymerase, which is encoded by rpoB. Resistance through mutations in rpoB in Mycobacterium tuberculosis arises with a high frequency, estimated as 2.3  10 8 [76]. The mechanisms include point mutations, deletions and insertions [77], most of which occur in a small region of less than 100 bp; less than 5% occur outside of this region [78]. Mutations involving 8 conserved amino acids clustered within a region of 23 amino acids have been identified in rifampicin-resistant isolates of diverse geographical origin. Thus, substitution of a small number of highly conserved amino acids appears to be responsible for bsingle stepQ high-level

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resistance to rifampicin in M. tuberculosis. PCRbased methods directed at mutations in rpoB have been devised to detect rifampicin-resistance in M. tuberculosis [79].

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mia isolates through this mutation has been observed over a period of 6 months of use [94]. Other modifications in 23S rRNA found in linezolid-resistant strains include mutations in E. coli mutants at positions 2032 and 2447 which are closer to the A site [95].

7. Ribosomes 7.1. Methylation and mutation of 23S rRNA, mutation of 50S ribosomal proteins The macrolide, lincosamide and streptogramin B group of antibiotics block protein synthesis in bacteria by binding to the 50S ribosomal subunit [80]. Resistance to these antibiotics is referred to as MLS(B) type resistance and occurs in a wide range of Gram-positive and Gram-negative bacteria [81]. It results from a post-transcriptional modification of the 23S rRNA component of the 50S ribosomal subunit involving methylation or dimethylation of key adenine bases in the peptidyl transferase functional domain. In E. coli, base A2058 of the 23S rRNA is the target of methylation. Methylation is catalysed by adenine-specific Nmethyltransferases specified by the erm class of genes (erythromycin ribosome methylation), present in a wide range of organisms and frequently plasmidencoded. Mutations in 23S rRNA close to the sites of methylation have also been associated with resistance to the macrolide group of antibiotics in a range of organisms [82–84]. In addition to multiple mutations in the 23S rRNA, alterations in the L4 and L22 proteins of the 50S subunit have been reported in macrolide-resistant S. pneumoniae [85,86]. The ketolide, telithromycin retains activity against isolates that derive their resistance from these mechanisms [87,88]. The mechanism of action of oxazolidinones (for example, linezolid) involves multiple stages in protein synthesis. Although they bind to the 50S subunit, the effects include inhibition of formation of the initiation complex and interference with translocation of peptidyl-tRNA from the A site to the P site [89,90]. Resistance has been reported in a number of organisms including enterococci [91] and is linked to mutations in the 23S rRNA resulting in decreased affinity for binding [92,93]. Most mutations involve G to U substitutions in the peptidyl transferase region of 23S rRNA at position 2576, which forms part of the P site. A decrease in linezolid sensitivity of VRE bacterae-

7.2. Mutation of 16S rRNA and 30S ribosomal subunit proteins Aminoglycosides bind to the 16S rRNA in the smaller subunit of the bacterial ribosome, perturbing decoding of the mRNA [96]. Mutations in the 16S rRNA gene confer resistance to the aminoglycosides [97]. Substitutions at positions 1400, 1401, and 1483 have been found in some kanamycin-resistant clinical isolates of Mycobacterium smegmatis and M. tuberculosis but not in sensitive isolates. The most frequent substitution, from A to G, occurred at position 1400 [98]. Clinical isolates of Mycobacterium abscessus highly resistant to amikacin, kanamycin, gentamicin, tobramycin and neomycin have an A to G substitution at position 1408 [99]. This organism has only one copy of the rRNA operon whereas most organisms possess multiple copies, presumably requiring similar substitutions in each for full resistance. Chromosomally acquired streptomycin resistance in M. tuberculosis is frequently due to mutations in the rpsL gene encoding the ribosomal protein S12 together with changes in the rrs (16S rRNA)-coding region [100,101].

8. Mycolic acid synthesis in M. tuberculosis involving katG, inhA and kasA Isoniazid is a prodrug that is activated by the katGencoded catalase-peroxidase inside M. tuberculosis to generate free radicals that attack multiple targets in the cells [102]. Two important targets that are inhibited are an NADH-dependent enoyl acyl carrier protein (ACP) reductase encoded by inhA, and a h-ketoacyl ACP synthase encoded by kasA. Both of these enzymes are involved in the biosynthesis of mycolic acids [103,104]. Resistance-associated amino acid substitutions have been identified in the katG, inhA, and kasA genes of isoniazid-resistant clinical isolates of M. tuberculosis [105–107].

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9. Enoyl reductase encoded by fabI The antibacterial agents triclosan and hexachlorophene are inhibitors of the bacterial enoyl reductase encoded by fabI [108,109]. This enzyme catalyzes a key stage in the fatty acid biosynthesis cycle, the reduction of h-unsaturated fatty acids esterified to the acyl carrier protein (ACP). The FabI enzymes from E. coli and S. aureus have similar activities but use different cofactors, NADH for E. coli and NADPH for S. aureus [110]. Triclosan and hexachlorophene inhibit both enzymes. Although FabI is related to InhA of M. tuberculosis (36% identical and 67% similar) the enzymes show different sensitivities to inhibitors. Triclosan is a relatively weak inhibitor of InhA compared to FabI [111]. A number of mutations in the FabI enzyme result in resistance to triclosan with retention of normal function. Three mutations of FabI that result in amino acid substitutions (G93V, M159T, and F203L) correlate with triclosan resistance, showing increases in minimum inhibitory concentration (MIC) of 95-, 12-, and 6fold, respectively [112]. The enzyme with the G93V mutation showed a 9000-fold reduced affinity for triclosan with little effect on its enoyl reductase activity. Crystal structure determination has shown how the G93V substitution obstructs the triclosanbinding site, inhibiting formation of the ternary complex between the inhibitor, the enzyme and the cofactor [109,113].

Single and multiple mutations of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthetase bifunctional enzyme have been linked to antifolate resistance in malaria. Mutations involving residues 51, 59, 108, or 164 conferred cross-resistance to pyrimethamine and cycloguanil, whereas mutation of residue 16 specifically conferred resistance to cycloguanil [122]. Crystal structures of the sensitive and resistant enzymes reveal features responsible for resistance, including changes in the regions between the dihydrofolate reductase and thymidylate synthestase domains [123].

11. Pyrazinamidase Although pyrazinamidase is not the target of pyrazinamide, it is responsible for the anti-mycobacterial activity of this drug. Hydrolysis of pyrazinamide inside the cells and failure to efflux the resulting pyrazinoic acid lead to internal acidification and death of the organism [124]. Mutations in the pncA gene resulting in loss of pyrazinamidase activity have been linked to pyrazinamide resistance in M. tuberculosis in isolates from many countries [125–128]. Understanding of the mechanisms involved in pyrazinamide hydrolysis and the role of mutations involved in resistance may be derived from the crystal structure of pyrazinamidase from Pyrococcus horikoshii, which shows extensive homology with the enzyme from M. tuberculosis [129].

10. Dihydrofolate reductase 12. Iso-leucyl-tRNA synthetase Mutation in the dhfr gene producing single amino acid substitution in the dihydrofolate reductase target enzyme is responsible for trimethoprim resistance in S. aureus [114] and S. pneumoniae [115]. Changes in both the promoter and coding regions of the dhfr gene have been found in resistant strains of H. influenzae [116]. Over 20 different transferable trimethoprim-resistant dhfr genes have been characterized among Gram-negative bacteria [117]. They are efficiently spread as cassettes in integrons, and on transposons and plasmids [118– 120]. Transferable trimethoprim-resistant dhfr genes have also been observed in Gram-positive bacteria [121].

Mupirocin resistance in S. aureus results from changes in the target enzyme, isoleucyl-tRNA synthetase [130,131]. High-level resistance (MIC 512 Ag/ml) is plasmid-mediated, involving acquisition of a second mupirocin-resistant isoleucyl-tRNA synthetase gene, mupA [132]. Low-level resistance in clinical isolates (MIC = 8 to 256 Ag/ml) and in strains trained in vitro to high-level resistance results from point mutations in the chromosomal isoleucyl-tRNA synthetase gene, ileS [133,134]. Point mutations producing Val-to-Phe changes at either residue 588 (V588F) or residue 631 (V631F) of the synthetase have been identified in resistant S. aureus strains [135].

P.A. Lambert / Advanced Drug Delivery Reviews 57 (2005) 1471–1485

13. Elongation factor G Fusidic acid blocks bacterial protein synthesis in staphylococci by interfering with the function of elongation factor G (EF-G). Resistance to fusidic acid in S. aureus results from alterations in the target that appear in natural mutants and that are harboured at low rates in normal populations of staphylococci [136]. Point mutations within the chromosomal fusA gene encoding EF-G have been identified in clinical and labselected fusidic acid-resistant isolates [137], and P406L, H457Y and L461K changes in EF-G constructed by site-directed mutagenesis have been shown to elevate the fusidic acid MIC in sensitive laboratory strains to those seen in resistant clinical isolates [137].

14. Lipopolysaccharide The polymyxin antibiotics polymyxin B and colistin E exert their action by binding initially to the lipopolysaccharide (LPS) component of the outer membrane. Disruption of the outer membrane structure results in loss of its barrier function. The polymyxins can then cross the cell wall and bind to phopholipids in the cytoplasmic membrane, causing loss of membrane integrity leakage of cytoplasmic contents and cell death. The key initial interaction between polymyxins and LPS can be blocked by a modification of the phosphate esters linked to the diglucosamine components of the lipid A region. The chemical modification involves addition of 4aminoarabinose groups to the phosphate esters and is regulated by a two-component signal transduction system that responds to environmental conditions, including the presence of cationic antimicrobial peptides [138,139]. A related PmrA/PmrB regulatory system in Salmonella enterica controls the modification of lipid A with aminoarabinose and phosphoethanolamine, resulting in resistance to polymyxin B [140]. A number of enzymes involved in LPS biosynthesis have been investigated as targets for the design of novel agents against Gram-negative bacteria. UDP-3O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have been shown to have antibiotic activity

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[141,142] but the potential for resistance development through mutational changes in lpxC exists [141].

15. Conclusions Antibiotic resistance resulting from changes in the target structure presents a major problem to control of infectious disease, especially in the cases of MRSA, VRE, multidrug-resistant M. tuberculosis and some multi-resistant Gram-negative bacteria. The emergence of VISA and VRSA clearly signals the urgent need to develop more effective agents. One approach to meet this challenge is the continued, incremental improvement of existing classes of antibiotics, for example h-lactams that retain their activity against low affinity PBPs [10–17] and glycopeptides such as oritavancin, telavancin and dalbavancin that retain activity against VRE [59–62]. Continued development of the more recently introduced agents such as the oxazolidinones, ketolides, azalides, streptogramins and glycylcyclines will be necessary to keep ahead of the inevitable resistance development. Understanding the mechanisms of action of existing antibiotics could be used to identify new targets, for example in peptidoglycan, protein and DNA synthesis, and re-evaluation of the potential of existing agents is also worthwhile [143]. New classes of agent such as the peptide deformylase (PDF) inhibitors may have an impact upon the control of drug-resistant organisms [144]. However, it is clear at this early stage in the development of these agents that resistance can occur through mutational changes in the essential defB deformylase gene [145–147]. Finally, whilst genome-driven drug discovery undoubtedly offers exciting potential [148], serendipitous observations continue to provide significant opportunities, as illustrated by the effects of the plant-derived catechins in restoring methicillin sensitivity in MRSA [149].

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