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J. Biol. Chem., Vol. 282, Issue 48, 35143-35152, November 30, 2007

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Diversity of Penicillin-binding Proteins

RESISTANCE FACTOR FmtA OF STAPHYLOCOCCUS AUREUS^*

Xin Fan, Yuhong Liu, Daryl Smith^¶, Lars Konermann, K. W. Michael Siu^¶, and Dasantila Golemi-Kotra¹

From the Department of Chemistry, ^¶Center for Research in Mass Spectrometry, York University, Toronto, Ontario M3J 1P3 and Department of Chemistry, University of Western Ontario, London, Ontario N6A 5B7, Canada

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 may be 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.

Received for publication, July 31, 2007 , and in revised form, September 25, 2007.

^* This work is supported in part by a grant (to D. G.-K.) from the Natural Sciences and Engineering Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Chemistry, York University, Toronto, ON, M3J 1P3, Canada. Tel.: 416-736-2100; Fax: 416-736-5936; E-mail: dgkotra{at}yorku.ca.

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