HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 15, 10035-10041, April 14, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/15/10035    most recent M508846200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fuda, C. Articles by Mobashery, S. Search for Related Content PubMed PubMed Citation Articles by Fuda, C. Articles by Mobashery, S. Social Bookmarking                      What's this?

Mechanistic Basis for the Action of New Cephalosporin Antibiotics Effective against Methicillin- and Vancomycin-resistant Staphylococcus aureus^*

Cosimo Fuda, Dusan Hesek, Mijoon Lee, Werner Heilmayer, Rodger Novak, Sergei B. Vakulenko, and Shahriar Mobashery¹

From the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556 and Antibiotic Research Institute, Sandoz GmbH, Brunner Strasse, A-1235 Vienna, Austria

Emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created challenges in treatment of nosocomial infections. The recent clinical emergence of vancomycin-resistant MRSA is a new disconcerting chapter in the evolution of these strains. S. aureus normally produces four PBPs, which are susceptible to modification by-lactam antibiotics, an event that leads to bacterial death. The gene product of mecA from MRSA is a penicillin-binding protein (PBP) designated PBP 2a. PBP 2a is refractory to the action of all commercially available -lactam antibiotics. Furthermore, PBP 2a is capable of taking over the functions of the other PBPs of S. aureus in the face of the challenge by -lactam antibiotics. Three cephalosporins (compounds 1–3) have been studied herein, which show antibacterial activities against MRSA, including the clinically important vancomycin-resistant strains. These cephalosporins exhibit substantially smaller dissociation constants for the preacylation complex compared with the case of typical cephalosporins, but their pseudo-second-order rate constants for encounter with PBP 2a (k₂/K_s) are not very large (200 M^–1 s^–1). It is documented herein that these cephalosporins facilitate a conformational change in PBP 2a, a process that is enhanced in the presence of a synthetic surrogate for cell wall, resulting in increases in the k₂/K_s parameter and in more facile enzyme inhibition. These findings argue that the novel cephalosporins are able to co-opt interactions between PBP 2a and the cell wall in gaining access to the active site in the inhibition process, a set of events that leads to effective inhibition of PBP 2a and the attendant killing of the MRSA strains.

Received for publication, August 10, 2005 , and in revised form, February 3, 2006.

^* This research was supported by a grant from the National Institutes of Health (NIH). The Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) program is supported by NIAID, NIH, Contract NO1-AI-95359. 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.

¹ To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. Tel.: 574-631-6652; Fax: 574-631-2933; E-mail: mobashery{at}nd.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. L. Fernandez, M. Cartelle, L. Muriel, R. Santiso, M. Tamayo, V. Goyanes, J. Gosalvez, and G. Bou DNA Fragmentation in Microorganisms Assessed In Situ Appl. Envir. Microbiol., October 1, 2008; 74(19): 5925 - 5933. [Abstract] [Full Text] [PDF]

				M. Chung, A. Antignac, C. Kim, and A. Tomasz Comparative Study of the Susceptibilities of Major Epidemic Clones of Methicillin-Resistant Staphylococcus aureus to Oxacillin and to the New Broad-Spectrum Cephalosporin Ceftobiprole Antimicrob. Agents Chemother., August 1, 2008; 52(8): 2709 - 2717. [Abstract] [Full Text] [PDF]

				S. Lemaire, C. Fuda, F. Van Bambeke, P. M. Tulkens, and S. Mobashery Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to {beta}-Lactam Antibiotics by Acidic pH: ROLE OF PENICILLIN-BINDING PROTEIN PBP 2a J. Biol. Chem., May 9, 2008; 283(19): 12769 - 12776. [Abstract] [Full Text] [PDF]

				S. Lemaire, F. Van Bambeke, M.-P. Mingeot-Leclercq, Y. Glupczynski, and P. M. Tulkens Role of Acidic pH in the Susceptibility of Intraphagocytic Methicillin-Resistant Staphylococcus aureus Strains to Meropenem and Cloxacillin Antimicrob. Agents Chemother., May 1, 2007; 51(5): 1627 - 1632. [Abstract] [Full Text] [PDF]