Structure of the covalent adduct formed between Mycobacterium tuberculosis β-lactamase and clavulanate

Lee W. Tremblay, Jean Emmanuel Hugonnet, John S. Blanchard

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Abstract

The intrinsic resistance of Mycobacterium tuberculosis to the β-lactam class of antibiotics arises from a chromosomally encoded, extended spectrum, class A β-lactamase, BlaC. Herein, we report the X-ray crystallographic structure of BlaC inhibited with clavulanate at a resolution of 1.7 Å with an R-factor value of 0.180 and R-free value of 0.212 for the mlz + 154 clavulanate-derived fragment observed in the active site. Structural evidence reveals the presence of hydrogen bonds to the C1 carbonyl along with a coplanar arrangement of C1, C2, C3, and N4, which favors enolization to generate a trans-α,β-eneamine, stabilizing the +154 adduct from hydrolysis. The irreversible inhibition of BlaC suggests that treatment of M. tuberculosis with a combination of a β-lactam antibiotic and clavulanate may lead to rapid bactericidal activity.

Original languageEnglish (US)
Pages (from-to)5312-5316
Number of pages5
JournalBiochemistry
Volume47
Issue number19
DOIs
StatePublished - May 13 2008

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ASJC Scopus subject areas

  • Biochemistry

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