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Antimicrobial Agents and Chemotherapy, June 2007, p. 2136-2142, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00866-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Competitive Inhibitors of the CphA Metallo-ß-Lactamase from Aeromonas hydrophila{triangledown}

L. E. Horsfall,1,{dagger} G. Garau,2,{dagger} B. M. R. Liénard,3 O. Dideberg,2 C. J. Schofield,3 J. M. Frère,1 and M. Galleni1*

Centre d'Ingéniérie des Protéines, Université de Liège, Allée de 6 Aout B6, Sart-Tilman, Liège, Belgium,1 Institut de Biologie Structurale Jean-Pierre Ebel (CNRS/CEA/UJF), 41 Rue J. Horowitz, Grenoble 38100, France,2 Chemistry Research Laboratory, 12 Mansfield Road, Oxford, United Kingdom3

Received 14 July 2006/ Returned for modification 8 October 2006/ Accepted 14 January 2007

Various inhibitors of metallo-ß-lactamases have been reported; however, none are effective for all subgroups. Those that have been found to inhibit the enzymes of subclass B2 (catalytically active with one zinc) either contain a thiol (and show less inhibition towards this subgroup than towards the dizinc members of B1 and B3) or are inactivators behaving as substrates for the dizinc family members. The present work reveals that certain pyridine carboxylates are competitive inhibitors of CphA, a subclass B2 enzyme. X-ray crystallographic analyses demonstrate that pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner within the active site. Salts of these compounds are already available and undergoing biomedical testing for various nonrelated purposes. Pyridine carboxylates appear to be useful templates for the development of more-complex, selective, nontoxic inhibitors of subclass B2 metallo-ß-lactamases.

* Corresponding author. Mailing address: Centre d'Ingéniérie des Protéines, Université de Liège, Allée de 6 Aout B6, Sart-Tilman, Liège, Belgium. Phone: 3243663549. Fax: 3243663364. E-mail: mgalleni{at}ulg.ac.be

{triangledown} Published ahead of print on 16 February 2007.

{dagger} These authors contributed equally to this work.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2136-2142, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00866-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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