title: Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.
abstract: Although isoniazid (isonicotinic acid hydrazide, INH) is widely used for the treatment of tuberculosis, its molecular target has remained elusive. In response to INH treatment, saturated hexacosanoic acid (C26:0) accumulated on a 12-kilodalton acyl carrier protein (AcpM) that normally carried mycolic acid precursors as long as C50. A protein species purified from INH-treated Mycobacterium tuberculosis was shown to consist of a covalent complex of INH, AcpM, and a beta-ketoacyl acyl carrier protein synthase, KasA. Amino acid-altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug.
authors.affiliation: Tuberculosis Research Unit, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health, Hamilton, MT 59840, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mdluli
authors.forename: R A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: S
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: X
authors.initials: X
authors.lastname: Pan
authors.forename: D
authors.initials: D
authors.lastname: Mead
authors.forename: D D
authors.initials: DD
authors.lastname: Crane
authors.forename: J M
authors.initials: JM
authors.lastname: Musser
authors.forename: C E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000213:Acyl Carrier Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005798:Genes, Bacterial; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D009171:Mycolic Acids / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology; D015854:Up-Regulation
chemical_list: D000213:Acyl Carrier Protein; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D009171:Mycolic Acids; C017364:hexacosanoic acid; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D007538:Isoniazid