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

Abstract

Objectives: This study evaluated the affinity of ceftaroline and comparator β-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 (IC50s) 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 β-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. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.