JAC Advance Access published online on January 19, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh550
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1 Centre de Recherche sur la Fonction, Structure et Ingénierie des Protéines, Faculté de Médecine, Pavillon Charles-Eugène-Marchand, Université Laval, Sainte-Foy, Québec, Canada G1K 7P4
* To whom correspondence should be addressed. Objectives: In Gram-negative bacteria, resistance to Methods: The L-1 metalloenzyme from Stenotrophomonas maltophilia was cloned, over-expressed, purified to homogeneity and used in screening of peptide libraries by phage display with a selective and competitive biopanning assay. This was based upon the high affinity of L-1 for cefoxitin and its slow hydrolysis. Results: From six peptides, the consensus sequence Cys-Val-His-Ser-Pro-Asn-Arg-Glu-Cys was identified as a promising inhibitor of L-1 hydrolytic activity. This peptide showed a mixed inhibition of L-1 with a Ki competitive of 16 ± 4 µM and a Ki uncompetitive of 9 ± 1 µM. The same peptide was prepared without flanking Cys residues and demonstrated no detectable inhibition of L-1 hydrolytic activity with nitrocefin as a substrate. These data confirmed the importance of the peptide conformation for the inhibition of L-1 hydrolytic activity. Further analysis revealed rescue by Zn2+ ions. The mixed inhibition indicated peptide binding near the active site of L-1 and blocking of zinc atoms for optimal conformation in the pocket of the active site. Conclusion: This is the first report of a peptide inhibitor for Class B metallo-
Received August 25, 2004
Revised November 10, 2004
Accepted November 24, 2004
Brief report
A specific peptide inhibitor of the class B metallo-
-lactamase L-1 from Stenotrophomonas maltophilia identified using phage display
Roger C. Levesque, E-mail: rclevesq{at}rsvs.ulaval.ca
Abstract 
-lactam antibiotics and to known inhibitors mediated by metallo--lactamases is a major concern and a serious threat to public health. Since no clinically useful inhibitors are available against class B metallo--lactamases, the aim of the study was to identify peptides as inhibitors.-lactamases. It will be used as a lead to identify more potent small molecule inhibitors via peptidomimetics.-lactamase; selective biopanning; -lactamase inhibitors.
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