Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis

The cellular mycolate synthetase activity of Mycobacterium tuberculosis H37Ra was previously shown to be very sensitive to isoniazid (Wang, L., and K. Takayama. 1972. Antimicrob. Agents Chemother. 2: 438-441). We have now examined the question of how isoniazid inhibits the synthesis of mycolic acids...

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Bibliographic Details
Published in:Journal of lipid research 1975-07, Vol.16 (4), p.308-317
Main Authors: Takayama, K, Schnoes, H K, Armstrong, E L, Boyle, R W
Format: Article
Language:English
Subjects:
Acetates - metabolism
Chromatography, Gas
Chromatography, Gel
Fatty Acids - biosynthesis
Isoniazid - pharmacology
Molecular Weight
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - metabolism
Mycolic Acids - metabolism
Structure-Activity Relationship
Temperature
Time Factors
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Summary:The cellular mycolate synthetase activity of Mycobacterium tuberculosis H37Ra was previously shown to be very sensitive to isoniazid (Wang, L., and K. Takayama. 1972. Antimicrob. Agents Chemother. 2: 438-441). We have now examined the question of how isoniazid inhibits the synthesis of mycolic acids. The saponifiable 14-C-labeled lipids of control and isoniazid-treated cells (1.0 mug/ml, 60 min) were compared on a Sephadex LH-20 column, and it appeared that the synthesis of the intermediate-sized fatty acids was partially inhibited. These fatty acids were fractionated as their methyl esters by Sephadex LH-20 column chromatograp-y and gas-liquid (6% Dexsil) chromatography. Mass sectral analysis of the fractionated lipids revealed several series of fatty acids: fraction II, C39-C56; fraction III, C27-C40. The long-chain fatty acids in three kinds of isoniazid-treated cells were examined: (a) long-term exposure (48 hr, 0.5 mug/ml), (b) short-term exposure (60 min, 1.0 mug/ml), and (c) variable exposure at low concentration (0-90 min, 0.2 mug/ml). Both long- and short-term exposure experiments showed that isoniazid inhibited the synthesis of saturated fatty acids greater than C26 and of unsaturated fatty acids greater than C24. The variable-exposure experiment at low isoniazid concentration showed that the syntheses of mycolic acids and long-chain fatty acid fractions II and III were inhibited to the same extent. These fatty acids may thus be precursors of mycolic acids.
ISSN:0022-2275
DOI:10.1016/s0022-2275(20)36719-5