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• W2377866320 abstract "New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium tuberculosis (Mtb). We report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as TBL-140, which has a minimal inhibitory concentration (MIC99) of 1.2 μg/mL. TBL-140 is effective against drug-resistant Mtb and nonreplicating bacteria. In addition, TBL-140 eliminates expansion of Mtb in cell culture infection assays at its MIC. To define the mechanism of action of this compound, we performed a spontaneous mutant screen and biochemical assays. We determined that TBL-140 treatment affects the proton motive force (PMF) by perturbing the transmembrane potential (ΔΨ), consistent with a target in the electron transport chain (ETC). As a result, treated bacteria have reduced intracellular ATP levels. We show that TBL-140 exhibits greater metabolic stability than SQ109, a structurally similar compound in clinical trials for treatment of MDR-TB infections. Combined, these results suggest that TBL-140 should be investigated further to assess its potential as an improved therapeutic lead against Mtb." @default.
• W2377866320 created "2016-06-24" @default.
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• W2377866320 date "2016-05-13" @default.
• W2377866320 modified "2023-10-01" @default.
• W2377866320 title "Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against <i>Mycobacterium tuberculosis</i>" @default.
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• W2377866320 doi "https://doi.org/10.1021/acsinfecdis.6b00052" @default.
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