Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis
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- 作者：Marie H. Foss ; Sovitj Pou ; Patrick M. Davidson ; Jennifer L. Dunaj ; Rolf W. Winter ; Sovijja Pou ; Meredith H. Licon ; Julia K. Doh ; Yuexin Li ; Jane X. Kelly ; Rozalia A. Dodean ; Dennis R. Koop ; Michael K. Riscoe ; Georgiana E. Purdy
- 刊名：ACS Infectious Diseases
- 出版年：2016
- 出版时间：July 8, 2016
- 年：2016
- 卷：2
- 期：7
- 页码：500-508
- 全文大小：460K
- ISSN：2373-8227
文摘
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.