Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 14, Pages 7325-7333Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.708172
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Funding
- National Institutes of Health [AI074824]
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Cholest-4-en-3-one, whether added exogenously or generated intracellularly from cholesterol, inhibits the growth of Mycobacterium tuberculosis when CYP125A1 and CYP142A1, the cytochrome P450 enzymes that initiate degradation of the sterol side chain, are disabled. Here we demonstrate that a 16-hydroxy derivative of cholesterol, which was previously reported to inhibit growth of M. tuberculosis, acts by preventing the oxidation of the sterol side chain even in the presence of the relevant cytochrome P450 enzymes. The finding that (25R)-cholest-5-en-3 beta,16 beta,26-triol (1) (and its 3-keto metabolite) inhibit growth suggests that cholesterol analogs with non-degradable side chains represent a novel class of anti-mycobacterial agents. In accord with this, two cholesterol analogs with truncated, fluorinated side chains have been synthesized and shown to similarly block the growth in culture of M. tuberculosis.
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