Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis.
Genetic and biochemical evidence has implicated two different target enzymes for isoniazid (INH) within the unique type II fatty acid synthase (FAS) system involved in the production of mycolic acids. These two components are an enoyl acyl carrier protein (ACP) reductase, InhA, and a beta-ketoacyl-ACP synthase, KasA. We compared the consequences of INH treatment of Mycobacterium tuberculosis (MTB) with two inhibitors having well-defined targets: triclosan (TRC), which inhibits InhA; and thiolactomycin (TLM), which inhibits KasA. INH and TLM, but not TRC, upregulate the expression of an operon containing five FAS II components, including kasA and acpM. Although all three compounds inhibit mycolic acid synthesis, treatment with INH and TLM, but not with TRC, results in the accumulation of ACP-bound lipid precursors to mycolic acids that were 26 carbons long and fully saturated. TLM-resistant mutants of MTB were more cross-resistant to INH than TRC-resistant mutants. Overexpression of KasA conferred more resistance to TLM and INH than to TRC. Overexpression of InhA conferred more resistance to TRC than to INH and TLM. Co-overexpression of both InhA and KasA resulted in strongly enhanced levels of INH resistance, in addition to cross-resistance to both TLM and TRC. These results suggest that these components of the FAS II complex are not independently regulated and that alterations in the expression level of InhA affect expression levels of KasA. Nonetheless, INH appeared to resemble TLM more closely in overall mode of action, and KasA levels appeared to be tightly correlated with INH sensitivity.
Slayden
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Tuberculosis Research Section, Twinbrook II, Room 239, Laboratory of Host Defenses,12441 Parklawn Drive, NIAID, Rockville, MD 20852, USA.
Lee
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RE
Barry
C E
CE
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D004352:Drug Resistance, Microbial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054889:Fatty Acid Synthase, Type II; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009876:Operon; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D014260:Triclosan / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008055:Lipids; D009097:Multienzyme Complexes; D013876:Thiophenes; D014260:Triclosan; C035068:thiolactomycin; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D000123:Acetyltransferases; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D054889:Fatty Acid Synthase, Type II; D007538:Isoniazid