Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-beta-lactamases

Patricia Lassaux, Matthieu Hamel, Mihaela Gulea, Heinrich Delbrueck, Paola Sandra Mercuri, Louise Horsfall, Dominique Dehareng, Michael Kupper, Jean-Marie Frere, Kurt Hoffmann, Moreno Galleni, Carine Bebrone

Research output: Contribution to journalArticlepeer-review

Abstract

Although commercialized inhibitors of active site serine beta-lactamases are currently used in coadministration with antibiotic therapy, no clinically useful inhibitors of metallo-beta-lactamases (MBLs) have yet been discovered. In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of la, behaved as competitive inhibitors for the three subclasses. Apart from 13 and 21, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (K-i < 15 mu M). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor. The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn2+ ion, respectively. Molecular modeling studies of the interactions between compounds 10a and 18 and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.

Original languageEnglish
Pages (from-to)4862-4876
Number of pages15
JournalJournal of Medicinal Chemistry
Volume53
Issue number13
Early online date8 Jun 2010
DOIs
Publication statusPublished - 8 Jul 2010

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