Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae

J Antimicrob Chemother. 2010 Apr;65(4):713-6. doi: 10.1093/jac/dkp503. Epub 2010 Jan 22.

Abstract

Objectives: This study evaluated the affinity of ceftaroline and comparator beta-lactams for penicillin-binding proteins (PBPs) of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and Streptococcus pneumoniae with varying susceptibility to penicillin. Ceftaroline is currently in Phase 3 development for the treatment of complicated skin and skin structure infections and community-acquired pneumonia, including infections caused by MRSA and multidrug-resistant S. pneumoniae.

Methods: Binding affinities (IC(50)s) of ceftaroline, ceftriaxone, oxacillin and penicillin G for PBPs were measured in a competition assay by adding various concentrations of the test drugs to membranes or whole cells. PBPs were labelled using the fluorescent reporter molecule Bocillin FL.

Results: Overall, ceftaroline exhibited greater binding affinity for the range of PBPs tested, as compared with comparator beta-lactams. The high affinity of ceftaroline for PBPs 1-3 of MSSA and PBP2a of MRSA correlates well with its efficacy against these organisms, as determined by MIC. Similarly, efficient binding of ceftaroline to key S. pneumoniae PBPs, such as PBP2x/2a/2b, taken together, correlates well with its low MICs for penicillin-resistant isolates of S. pneumoniae.

Conclusions: The high affinities of ceftaroline for MRSA PBP2a, MSSA PBPs 1-3 and S. pneumoniae PBP2x/2a/2b support the potential efficacy of ceftaroline in the treatment of infections caused by MRSA and S. pneumoniae.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology
  • Cephalosporins / metabolism*
  • Cephalosporins / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Penicillin-Binding Proteins / metabolism*
  • Protein Binding
  • Staphylococcus aureus / drug effects*
  • Streptococcus pneumoniae / drug effects*

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • Penicillin-Binding Proteins
  • T 91825