Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.
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.
Mdluli
K
K
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.
Slayden
R A
RA
Zhu
Y
Y
Ramaswamy
S
S
Pan
X
X
Mead
D
D
Crane
D D
DD
Musser
J M
JM
Barry
C E
CE
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
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