title: Diversity of penicillin-binding proteins. Resistance factor FmtA of Staphylococcus aureus.
abstract: Antibiotic-resistant Staphylococcus aureus is a major concern to public health. Methicillin-resistant S. aureus strains are completely resistant to all beta-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 beta-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 beta-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 beta-lactamases) is the active-site nucleophile during the formation of acyl-enzyme species. FmtA has a low binding affinity for beta-lactams, and it experiences a slow acylation rate, suggesting that this protein is intrinsically resistant to beta-lactam inactivation. We found that FmtA undergoes conformational changes in presence of beta-lactams that may be essential to the beta-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 beta-lactam induced cell wall stress conditions.
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Daryl
authors.initials: D
authors.lastname: Smith
authors.forename: Lars
authors.initials: L
authors.lastname: Konermann
authors.forename: K W Michael
authors.initials: KW
authors.lastname: Siu
authors.forename: Dasantila
authors.initials: D
authors.lastname: Golemi-Kotra
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism; D002942:Circular Dichroism; D019295:Computational Biology / Q000379:methods; D024881:Drug Resistance, Bacterial; D008712:Methicillin / Q000494:pharmacology; D008969:Molecular Sequence Data; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D047090:beta-Lactams / Q000737:chemistry
chemical_list: C526198:FmtA protein, Staphylococcus aureus; D046915:Penicillin-Binding Proteins; D011134:Polysaccharides; D047090:beta-Lactams; D008712:Methicillin