Binding of I3-Lactam Antibiotics to Penicillin-Binding Proteins in Methicillin-Resistant Staphylococcus aureus

Binding affinity of penicillin-binding proteins (PBP) of Staphylococcus aureus for several {3-lactamantibiotics wasexaminedin a methicillin-susceptible strain and in twomethicillin-resistant strains, one heterogeneous and one homogeneous, to determine relationships between PBP bind-ing and expression ofresistance. PBPs 1-4 had similar affinities in all three strains. PBP 2a affini-ties were similar in both resistant strains. For the susceptible strain and for the susceptible subpopulation of cells in the heterogeneous strain, growth inhibition correlated with binding to PBPs 1-3, suggesting that these PBPs mediate susceptibility in both. For resistant cells, growth inhibition correlated only with binding to PBP 2a, suggesting that this is the target in resistant cells. Determination of binding affinity for PBP 2a or the concentration that inhibits growth of the most resistant subpopulation ofcells should be included in evaluation of{3-lactamantibiotics for potential activity against methicillin-resistant strains of S. aureus. Penicillin-binding proteins (PBP) are membrane-bound en-zymes that catalyze cross-linking reactions in bacterial cell wall synthesis [1]. PBPs are targets of (j-Iactam antibiotics, which interfere with cell wall synthesis by binding covalentl