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Journal of Lipid Research, Vol 16, 308-317, Copyright © 1975 by Lipid Research, Inc.
K Takayama, HK Schnoes, EL Armstrong and RW Boyle
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.
ARTICLES
Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis
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