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J. Biol. Chem., Vol. 282, Issue 29, 21382-21391, July 20, 2007

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Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated -Lactam Resistance^*

Keith A. Stubbs, Misty Balcewich, Brian L. Mark, and David J. Vocadlo, Supported as a Tier II Canada Research Chair and as a Scholar of the Michael Smith Foundation for Health Research¹

From the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6 and the Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada

The increasing spread of plasmid-borne ampC-ampR operons is of considerable medical importance, since the AmpC -lactamases they encode confer high level resistance to many third generation cephalosporins. Induction of AmpC -lactamase from endogenous or plasmid-borne ampC-ampR operons is mediated by a catabolic inducer molecule, 1,6-anhydro-N-acetylmuramic acid (MurNAc) tripeptide, an intermediate of the cell wall recycling pathway derived from the peptidoglycan. Here we describe a strategy for attenuating the antibiotic resistance associated with the ampC-ampR operon by blocking the formation of the inducer molecule using small molecule inhibitors of NagZ, the glycoside hydrolase catalyzing the formation of this inducer molecule. The structure of the NagZ-inhibitor complex provides insight into the molecular basis for inhibition and enables the development of inhibitors with 100-fold selectivity for NagZ over functionally related human enzymes. These PUGNAc-derived inhibitors reduce the minimal inhibitory concentration (MIC) values for several clinically relevant cephalosporins in both wild-type and AmpC-hyperproducing strains lacking functional AmpD.

Received for publication, January 3, 2007 , and in revised form, March 6, 2007.

The atomic coordinates and structure factors (code 2OXN) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Canadian Institutes of Health Research and the Canadian Cystic Fibrosis Foundation. The structural aspects of this study were supported by 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.

¹ To whom correspondence should be addressed: Dept. of Chemistry, Simon Fraser University, 8888 University Dr., Burnaby, British Columbia V5A 1S6, Canada. Tel.: 604-291-3530; Fax: 604-291-3765; E-mail: dvocadlo{at}sfu.ca.

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This article has been cited by other articles:

				A. Asgarali, K. A. Stubbs, A. Oliver, D. J. Vocadlo, and B. L. Mark Inactivation of the Glycoside Hydrolase NagZ Attenuates Antipseudomonal {beta}-Lactam Resistance in Pseudomonas aeruginosa Antimicrob. Agents Chemother., June 1, 2009; 53(6): 2274 - 2282. [Abstract] [Full Text] [PDF]

				J. T. Park and T. Uehara How Bacteria Consume Their Own Exoskeletons (Turnover and Recycling of Cell Wall Peptidoglycan) Microbiol. Mol. Biol. Rev., June 1, 2008; 72(2): 211 - 227. [Abstract] [Full Text] [PDF]