Cholesterol analogs with degradation-resistant alkyl side chains are effective mycobacterium tuberculosis growth inhibitors
Authors: Daniel J. Frank, Yan Zhao, Siew Hoon Wong, Debashree Basudhar, James J. De Voss, Paul R. Ortiz de Montellano
Summary:
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-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 of M. tuberculosis.
Source: Journal of Biological Chemistry; 2016, 291 (14): 7325
Summary:
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-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 of M. tuberculosis.
Source: Journal of Biological Chemistry; 2016, 291 (14): 7325