Irreversible inhibition of the Mycobacterium tuberculosis β-lactamase by clavulanate

Jean Emmanuel Hugonnet, John S. Blanchard

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Members of the β-lactam class of antibiotics, which inhibit the bacterial D,D-transpeptidases involved in cell wall biosynthesis, have never been used systematically in the treatment of Mycobacterium tuberculosis infections because of this organism's resistance to β-lactams. The critical resistance factor is the constitutive production of a chromosomally encoded, Ambler class A β-lactamase, BlaC in M. tuberculosis. We show that BlaC is an extended spectrum β-lactamase (ESBL) with high levels of penicillinase and cephalosporinase activity as well as measurable activity with carbapenems, including imipenem and meropenem. We have characterized the enzyme's inhibition by three FDA-approved β-lactamase inhibitors: sulbactam, tazobactam, and clavulanate. Sulbactam inhibits the enzyme competitively and reversibly with respect to nitrocefin. Tazobactam inhibits the enzyme in a time-dependent manner, but the activity of the enzyme reappears due to the slow hydrolysis of the covalently acylated enzyme. In contrast, clavulanate reacts with the enzyme quickly to form hydrolytically stable, inactive forms of the enzyme that have been characterized by mass spectrometry. Clavulanate has potential to be used in combination with approved β-lactam antibiotics to treat multi-drug resistant (MDR) and extremely drug resistant (XDR) strains of M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)11998-12004
Number of pages7
JournalBiochemistry
Volume46
Issue number43
DOIs
StatePublished - Oct 30 2007

ASJC Scopus subject areas

  • Biochemistry

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