Transfer of a Point Mutation in Mycobacterium Tuberculosis inhA Resolves the Target of Isoniazid

Nat Med. 2006 Sep;12(9):1027-9. doi: 10.1038/nm1466. Epub 2006 Aug 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial / genetics
  • Isoniazid / pharmacology*
  • Mycobacterium tuberculosis / genetics*
  • Mycolic Acids / metabolism
  • NAD / metabolism
  • NAD / pharmacology
  • Oxidoreductases / genetics*
  • Oxidoreductases / metabolism
  • Point Mutation*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Mycolic Acids
  • NAD
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • Isoniazid