title: Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Arai
authors.forename: Manzour Hernando
authors.initials: MH
authors.lastname: Hazbón
authors.forename: Roberto
authors.initials: R
authors.lastname: Colangeli
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Torin R
authors.initials: TR
authors.lastname: Weisbrod
authors.forename: David
authors.initials: D
authors.lastname: Alland
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000235:genetics; D007538:Isoniazid / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D009171:Mycolic Acids / Q000378:metabolism; D009243:NAD / Q000378:metabolism / Q000494:pharmacology; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009171:Mycolic Acids; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid