b-lactams against methicillin-resistant Staphylococcus aureus Bertrand Guignard, Jose ´ M Entenza and Philippe Moreillon Methicillin-resistant Staphylococcus aureus (MRSA) have developed resistance to virtually all non-experimental antibiotics. They are intrinsically resistant to b-lactams by virtue of newly acquired low-affinity penicillin-binding protein 2A (PBP2A). Because PBP2A can build the wall when other PBPs are blocked by b-lactams, designing b-lactams capable of blocking this additional target should help solve the issue. Older molecules including penicillin G, amoxicillin and ampicillin had relatively good PBP2A affinities, and successfully treated experimental endocarditis caused by MRSA, provided that the bacterial penicillinase could be inhibited. Newer anti-PBP2A b-lactams with over 10-fold greater PBP2A affinities and low minimal inhibitory concentrations were developed, primarily in the cephem and carbapenem classes. They are also very resistant to penicillinase. Most have demonstrated anti-MRSA activity in animal models of infection, and two — the carbapenem CS-023 and the cephalosporin ceftopibrole medocaril — have proceeded to Phase II and Phase III clinical evaluation. Thus, clinically useful anti-MRSA b-lactams are imminent. Addresses University of Lausanne, Department of Fundamental Microbiology, Biology Building, 1015 Lausanne, Switzerland Corresponding author: Moreillon, Philippe (Philippe.Moreillon@unil.ch) Current Opinion in Pharmacology 2005, 5:479–489 This review comes from a themed issue on Anti-infectives Edited by Alisdair MacGowan and David Payne Available online 10th August 2005 1471-4892/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2005.06.002 Introduction Staphylococcus aureus can produce a wide variety of dis- eases, from relatively benign skin infections such as folliculitis and furunculosis, to deep-seated and life-threa- tening conditions including erysipelas, deep abscesses, osteomyelitis, pneumonia, sepsis and endocarditis [1]. S. aureus can also induce ‘distant’ diseases, where the organ- ism is remote from the infected site but produces toxins that are responsible for the symptoms [2]. The hetero- geneity of these diseases and the unique ability of S. aureus to develop resistance to antibacterial agents reflect its extraordinary capacity to adapt to a great variety of environments. The S. aureus genome revealed the exis- tence of many mobilisable DNA elements, including insertion sequences, transposons, bacteriophages and pathogenicity islands [3–5], which contain specific deter- minants responsible for disease and antibiotic resistance [5,6]. Methicillin resistance is associated with the mobile ele- ment SCCmec, where SCC stands for staphylococcal chromosomal cassette and mec for the gene encoding penicillin-binding protein (PBP)2A [7]. PBP2A has a low b-lactam affinity and confers resistance to most molecules of this family [8,9]. There are at least four major types of SCCmec that mirror the hospital-related and community-related ecology of methicillin-resistant Staphylococcus aureus (MRSA) clones [9,10,11]. In spite of this polymorphism, however, the gene for PBP2A is remarkably conserved [9–11]. This is critical for drug development. If PBP2A were to be a target for new antimicrobials, then it must be conserved among all methicillin-resistant isolates. b-Lactams and b-lactam-resistance b-lactams inhibit bacterial growth by interfering with cell wall assembly. They bind to the active site of a series of membrane-bound enzymes — the PBPs — responsible for inserting the peptidoglycan precursors into the nas- cent wall (Figure 1)[12,13]. Several of these PBPs are bifunctional and retain both a transglycosidase and a transpeptidase activity. S. aureus carries only one bifunc- tional PBP (PBP2) and three monofunctional transpepti- dases (PBP1, 3 and 4). Transpeptidation takes place at the D-ala-D-ala terminal of the precursor (Figure 1a). b-lactams are mechanism- based inhibitors of this transpeptidation step. They com- pete with the wall precursor for binding to the active site of the enzyme and undergo nucleophilic attack at their C O residue in a similar manner to the PBP natural D- ala-D-ala substrate. However, unlike natural D-ala-D-ala, the b-lactam-PBP acyl adduct is stable, resulting in irreversible blockage of PBP function. The most common mechanism of resistance of S. aureus to b-lactams is mediated by penicillinase, which hydrolyses penicillinase-susceptible compounds and is encoded by the blaZ gene, and which is usually carried on a plasmid (for review, see [12]). In addition, MRSA produce newly acquired PBP2A, which is a wall-building transpeptidase that resists blockage by b-lactams. PBP2A is an absolute requirement for high-level b-lactam-resistance in MRSA [8]. Blocking its activity in isolation, as in PBP2A- negative mutants, restores susceptibility to b-lactams. www.sciencedirect.com Current Opinion in Pharmacology 2005, 5:479–489