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Originally published In Press as doi:10.1074/jbc.M107054200 on September 19, 2001

J. Biol. Chem., Vol. 276, Issue 48, 45015-45023, November 30, 2001
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Thiomandelic Acid, a Broad Spectrum Inhibitor of Zinc beta -Lactamases
KINETIC AND SPECTROSCOPIC STUDIES*,

Claire MollardDagger §, Catherine Moali§, Cyril Papamicael§||, Christian DamblonDagger , Sandrine Vessilier**, Gianfranco Amicosante**, Christopher J. Schofield||, Moreno Galleni, Jean-Marie Frère, and Gordon C. K. RobertsDagger Dagger Dagger

From the Dagger  Biological NMR Centre, Department of Biochemistry, University of Leicester, P.O. Box 138, University Rd., Leicester LE1 9HN, United Kingdom,  Centre d'Ingénierie des Protéines, Institut de Chimie B6, Université de Liège, Sart-Tilman, B-4000 Liège, Belgium, || The Oxford Centre for Molecular Sciences and The Dyson Perrins Laboratory, South Parks Rd., Oxford OX1 3QY, United Kingdom, and ** Dipartimento di Scienze e Tecnologie Biomediche, Università dell'Aquila, L'Aquila I-67100, Italy

Resistance to beta -lactam antibiotics mediated by metallo-beta -lactamases is an increasingly worrying clinical problem. Candidate inhibitors include mercaptocarboxylic acids, and we report studies of a simple such compound, thiomandelic acid. A series of 35 analogues were synthesized and examined as metallo-beta -lactamase inhibitors. The Ki values (Bacillus cereus enzyme) are 0.09 µM for R-thiomandelic acid and 1.28 µM for the S-isomer. Structure-activity relationships show that the thiol is essential for activity and the carboxylate increases potency; the affinity is greatest when these groups are close together. Thioesters of thiomandelic acid are substrates for the enzyme, liberating thiomandelic acid, suggesting a starting point for the design of "pro-drugs." Importantly, thiomandelic acid is a broad spectrum inhibitor of metallo-beta -lactamases, with a submicromolar Ki value for all nine enzymes tested, except the Aeromonas hydrophila enzyme; such a wide spectrum of activity is unprecedented. The binding of thiomandelic acid to the B. cereus enzyme was studied by NMR; the results are consistent with the idea that the inhibitor thiol binds to both zinc ions, while its carboxylate binds to Arg91. Amide chemical shift perturbations for residues 30-40 (the beta 3-beta 4 loop) suggest that this small inhibitor induces a movement of this loop of the kind seen for other larger inhibitors.

* This work was supported by the European research network on metallo-beta -lactamases, within the Training and Mobility of Researchers program (contract ERBFMRXCT 980232), by the Wellcome Trust (Traveling Research Fellowship to C. F. D.), by the Biotechnology and Biological Sciences Research Council, and by the Belgian program Pôles d'Attraction Interuniversitaire Grant PAI P4/03.The costs of publication of this article were defrayed in part by the payment of page charges. The 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 two schemes and one figure.

§ These authors contributed equally to this work.

Dagger Dagger To whom correspondence should be addressed. Tel.: 44-116-252-2978; Fax: 44-116-223-1503; E-mail: gcr@le.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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