title: Cholesterol Analogs with Degradation-resistant Alkyl Side Chains Are Effective Mycobacterium tuberculosis Growth Inhibitors.
abstract: Cholest-4-en-3-one, whether added exogenously or generated intracellularly from cholesterol, inhibits the growth ofMycobacterium tuberculosiswhen 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 ofM. 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-3β,16β,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 ofM. tuberculosis.
authors.affiliation: From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517 and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Frank
authors.affiliation: From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517 and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: the School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia.
authors.forename: Siew Hoon
authors.initials: SH
authors.lastname: Wong
authors.affiliation: From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517 and.
authors.forename: Debashree
authors.initials: D
authors.lastname: Basudhar
authors.affiliation: the School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia.
authors.forename: James J
authors.initials: JJ
authors.lastname: De Voss
authors.affiliation: From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517 and ortiz@cgl.ucsf.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Ortiz de Montellano
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002783:Cholestenones / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000254:growth & development*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002783:Cholestenones; C116007:cytochrome P-450 CYP12A1 (house fly); D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol
keywords: Mycobacterium tuberculosis; cholesterol metabolism; cytochrome P450; dehydrogenase; enzyme inhibitor
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