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  • Title: A specific peptide inhibitor of the class B metallo-beta-lactamase L-1 from Stenotrophomonas maltophilia identified using phage display.
    Author: Sanschagrin F, Levesque RC.
    Journal: J Antimicrob Chemother; 2005 Feb; 55(2):252-5. PubMed ID: 15659541.
    Abstract:
    OBJECTIVES: In Gram-negative bacteria, resistance to beta-lactam antibiotics and to known inhibitors mediated by metallo-beta-lactamases is a major concern and a serious threat to public health. Since no clinically useful inhibitors are available against class B metallo-beta-lactamases, the aim of the study was to identify peptides as inhibitors. 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 K(i competitive) of 16 +/- 4 microM and a K(i uncompetitive) of 9 +/- 1 microM. 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-beta-lactamases. It will be used as a lead to identify more potent small molecule inhibitors via peptidomimetics.
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