Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid

Catherine Vilchèze, Feng Wang, Masayoshi Arai, Manzour Hernando Hazbón, Roberto Colangeli, Laurent Kremer, Torin R. Weisbrod, David Alland, James C. Sacchettini, William R. Jacobs

Research output: Contribution to journalArticlepeer-review

215 Scopus citations

Abstract

Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)1027-1029
Number of pages3
JournalNature Medicine
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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