Can beta-lactams be re-engineered to beat MRSA?

Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases
David M Livermore

Abstract

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. Cef...Continue Reading

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