Figure 1From: Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibioticsSchematic 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]).Back to article page