Cholesterol Analogs Block Growth of Tuberculosis Bacteria

Analogs of cholesterol that have been modified by the addition of non- degradable side chains have been shown to inhibit the growth of Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB).

Investigators at the University of Queensland (Brisbane, Australia) and the University of California, San Francisco (USA) had previously found that the cholesterol derivative cholest-4-en-3-one, whether added or generated intracellularly from cholesterol, inhibited the growth of M. tuberculosis when the cytochrome P450 enzymes (CYP125A1 and CYP142A1) that initiate degradation of the sterol side chain were disabled.

Continuing this line of research, they reported in the April 1, 2016, issue of the Journal of Biological Chemistry that a 16-hydroxy derivative of cholesterol, which was previously shown to inhibit growth of M. tuberculosis, acted 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-3beta,16beta,26-triol (1) (and its 3-keto metabolite) inhibited growth suggested that cholesterol analogs with non-degradable side chains represented a novel class of anti- mycobacterial agents.

To confirm this speculation, the investigators synthesized two cholesterol analogs with truncated, fluorinated side chains and demonstrated that these compounds could block the growth of M. tuberculosis in culture.

Contributing author Dr. James De Voss, professor of chemistry and molecular biosciences at the University of Queensland said, "If you give this bacterium modified cholesterol instead, then it cannot use it as its energy source and so it stops growing. Interestingly, we do not quite understand why this happens. Our discovery suggests a new way in which we can robustly inhibit growth of the TB bacterium."

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University of Queensland
University of California, San Francisco