Can beta-lactams be re-engineered to beat MRSA?
Methicillin-resistant Staphylococcus aureus (MRSA) strains are important nosocomial pathogens worldwide and now are also of growing importance in community-acquired infection. Their resistance depends upon a supplementary peptidoglycan transpeptidase, PBP2' (PBP-2a), which continues to function when normal PBPs have been inactivated by beta-lactams. PBP2' is encoded by the mecA gene, which is carried by the staphylococcal cassette chromosome, a large and somewhat variable DNA insert of uncertain origin. PBP2' does not wholly lack affinity for beta-lactams, but its affinity for available analogues is very weak. In principle, it should be possible to re-engineer beta-lactams to bind PBP2' strongly, and the desirability of this approach is self-evident: no other antibiotic class has a record equal to the beta-lactams for safety and efficacy. Moreover, there is consensus that beta-lactams are inherently more efficacious than vancomycin against infections due to susceptible staphylococci. In practice, finding viable PBP2'-active beta-lactams has proved difficult and the catalogue of near-misses extends back to the 1980s. At last, however, one cephalosporin with high affinity for PBP2'--ceftobiprole--is entering phase III trials. Ceftobiprole inhibits MRSA at 1-2 mg/L under standard conditions. Even when mecA/PBP2' was induced strongly, ceftobiprole MICs for MRSA only reached 4 mg/L, a clinically attainable concentration. A phase II trial in skin and skin structure infection recorded cures by ceftobiprole in 4/4 MRSA infections, and results of the phase III trials are awaited with great interest.
Livermore
D M
DM
Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London, UK. david.livermore@hpa.org.uk
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002511:Cephalosporins / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D016106:Methicillin Resistance; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D018440:beta-Lactam Resistance / Q000502:physiology; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D047090:beta-Lactams; C443755:ceftobiprole