Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis
Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis
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DOI：
10.1021/acsinfecdis.6b00052
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发表时间：
2016-07-01
影响因子：
5.3
通讯作者：
Purdy, Georgiana E.
中科院分区：
文献类型：
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作者：
Foss, Marie H.;Pou, Sovitj;Purdy, Georgiana E.
结核病感染的新治疗方法对于对抗多重耐药和广泛耐药结核分枝杆菌（Mtb）的出现至关重要。我们报告了二苯醚改性的金刚烷基1，2-二胺的表征，我们称之为TBL-140，其最小抑菌浓度（MIC 99）为1.2 μ g/mL。TBL-140对耐药性结核分枝杆菌和非复制型细菌有效。此外，TBL-140在其MIC下消除了细胞培养感染测定中Mtb的扩增。为了确定该化合物的作用机制，我们进行了自发突变体筛选和生化测定。我们确定TBL-140处理通过扰动跨膜电位（Delta Psi）影响质子动力（PMF），这与电子传递链（ETC）中的靶一致。结果，经处理的细菌具有降低的细胞内ATP水平。我们表明，TBL-140表现出更大的代谢稳定性比SQ 109，一个结构相似的化合物在临床试验中用于治疗耐多药结核病感染。结合，这些结果表明，TBL-140应进一步研究，以评估其作为抗结核分枝杆菌的改善治疗铅的潜力。
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 mu g/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 (Delta Psi), 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.