Publications by authors named "Joshua M Werman"

By illuminating key 6-azasteroid-protein interactions in both () and the closely related model organism (), we sought to improve the antimycobacterial potency of 6-azasteroids and further our understanding of the mechanisms responsible for their potentiation of the antituberculosis drug bedaquiline. We selected a newly developed 6-azasteroid analog and an analog reported previously ( , (7), 1239-1251) to study their phenotypic effects on and , both alone and in combination with bedaquiline. The 6-azasteroid analog, 17β-[-(4-trifluoromethoxy-diphenylmethyl)carbamoyl]-6-propyl-azaandrostan-3-one, robustly potentiated bedaquiline-mediated antimycobacterial activity, with a nearly 8-fold reduction in bedaquiline minimal inhibitory concentration (85 nM alone versus 11 nM with 20 μM 6-azasteroid).

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Whole cell-based phenotypic screens have become the primary mode of hit generation in tuberculosis (TB) drug discovery during the last two decades. Different drug screening models have been developed to mirror the complexity of TB disease in the laboratory. As these culture conditions are becoming more and more sophisticated, unraveling the drug target and the identification of the mechanism of action (MOA) of compounds of interest have additionally become more challenging.

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The unique ability of (Mtb) to utilize host lipids such as cholesterol for survival, persistence, and virulence has made the metabolic pathway of cholesterol an area of great interest for therapeutics development. Herein, we identify and characterize two genes from the Cho-region (genomic locus responsible for cholesterol catabolism) of the Mtb genome, (Rv3538) and (Rv3502c). Their protein products catalyze two sequential stereospecific hydration and dehydrogenation steps in the β-oxidation of the cholesterol side chain.

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Cholesterol is a major carbon source for () during infection, and cholesterol utilization plays a significant role in persistence and virulence within host macrophages. Elucidating the mechanism by which cholesterol is degraded may permit the identification of new therapeutic targets. Here, we characterized EchA19 (Rv3516), an enoyl-CoA hydratase involved in cholesterol side-chain catabolism.

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