Diversity of Penicillin-binding Proteins

Abstract

Antibiotic-resistant Staphylococcus aureus is a major concern to public health. Methicillin-resistant S. aureus strains are completely resistant to all β-lactams antibiotics. One of the main factors involved in methicillin resistance in S. aureus is the penicillin-binding protein, PBP2a. This protein is insensitive to inactivation by β-lactam antibiotics such as methicillin. Although other proteins are implicated in high and homogeneous levels of methicillin resistance, the functions of these other proteins remain elusive. Herein, we report for the first time on the putative function of one of these proteins, FmtA. This protein specifically interacts with β-lactam antibiotics forming covalently bound complexes. The serine residue present in the sequence motif Ser-X-X-Lys (which is conserved among penicillin-binding proteins and β-lactamases) is the active-site nucleophile during the formation of acyl-enzyme species. FmtA has a low binding affinity for β-lactams, and it experiences a slow acylation rate, suggesting that this protein is intrinsically resistant to β-lactam inactivation. We found that FmtA undergoes conformational changes in presence of β-lactams that maybe essential to the β-lactam resistance mechanism. FmtA binds to peptidoglycan in vitro. Our findings suggest that FmtA is a penicillin-binding protein, and as such, it may compensate for suppressed peptidoglycan biosynthesis under β-lactam induced cell wall stress conditions. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.