Figure 1

Schematic representation of the enzymatic steps involved in S. aureus cell wall synthesis and the targets of cell wall active antibiotics. Fosfomycin inhibits the enzyme MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase) that catalyses the addition of phosphoenolpyruvate (PEP) to UDP-N-acetyl-glucosamine (GlcNAc) to form UDP-N-acetyl-muramic acid (UDP-MurNAc) [34]. D-cycloserine prevents the addition of D-alanine to the peptidoglycan precursor by inhibiting D-alanine:D-alanine ligase A and alanine racemase [35]. Tunicamycin is a glycoprotein antibiotic that inhibits the transfer of peptidoglycan precursor (phospho-MurNAc-pentapeptide) to the lipid carrier undecaprenyl pyrophosphate (or C55-isoprenyl pyrophosphate), catalysed by the translocase MraY [36, 37]. Sub-lethal concentrations of tunicamycin also inhibit TarO, the first enzyme in the wall teichoic acid pathway [38, 39]. Bacitracin forms a metal-dependent complex with the lipid carrier undecaprenyl pyrophosphate, thereby preventing dephosphorylation and the recycling of the lipid carrier required for cell wall synthesis [40, 41]. Flavomycin (a moenomycin complex) is a phosphoglycolipid antibiotic that inhibits transglycosylation through binding of the transglycosylase domain of penicillin-binding protein 2 (PBP2) [42]. Glycopeptide antibiotics, such as vancomycin and teicoplanin, inhibit cell wall synthesis by binding the D-ala-D-ala of the lipid II and sterically hindering transglycosylation and transpeptidation. Teicoplanin activity is enhanced through its interaction with the cytoplasmic membrane [43]. ß-lactam antibiotics, such as oxacillin, bind the transpeptidase active domain of penicillin-binding proteins (PBPs) by mimicking the D-ala-D-ala end of the pentapeptide [44]. The mode of action of daptomycin is not fully known, it causes calcium-dependent disruption of membrane function and potassium efflux [45], but was also predicted to directly or indirectly inhibit peptidoglycan systhesis [9]. Lysostaphin is a zinc metalloenzyme that cleaves the pentaglycine crosslinking bridge specific for the cell wall of S. aureus [46]. (Adapted from [47]).