Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis
Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis
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DOI：
10.1093/jac/dkq313
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发表时间：
2010-10-01
影响因子：
5.2
通讯作者：
Bhakta, Sanjib
中科院分区：
文献类型：
--
作者：
Guzman, Juan D.;Gupta, Antima;Bhakta, Sanjib
临床上需要具有新作用机制的新型抗分枝杆菌实体来治疗耐药形式的结核病。本研究的目的是评估最近从哥伦比亚植物中分离的七种天然产物的抗结核活性和选择性。使用结核分枝杆菌 H(37)Rv 的液体培养基生长抑制测定法和牛分枝杆菌 BCG 的固体和液体培养基生长抑制测定法测定 MIC。评估了大肠杆菌生长抑制和哺乳动物巨噬细胞细胞毒性，以确定天然产物对全细胞生物体的选择性程度。使用比色磷酸盐检测方法测定了结核分枝杆菌 ATP 依赖性 MurE 连接酶的酶抑制。我们进一步研究了最活跃的化合物 3-methoxynordomesticine 盐酸盐对牛分枝杆菌 BCG 的乙状结肠生长抑制作用、抗酸染色和活力计数分析。发现阿朴啡生物碱是缓慢生长的分枝杆菌病原体的有效抑制剂，具有良好的选择性和细胞毒性。就其内源性作用而言，阿朴啡生物碱在微摩尔浓度下可抑制结核分枝杆菌 ATP 依赖性 MurE 连接酶。检测到 3-methoxynordomesticine 盐酸盐对牛分枝杆菌 BCG 和结核分枝杆菌 H(37)Rv 的 MIC 显着较低。考虑到所有数据，发现 3-methoxynordomesticine 盐酸盐是一种有效的抗结核化合物，具有良好的特异性。该生物碱表现出 MurE 抑制作用，被认为是探索相关化学空间的初步成果。
New anti-mycobacterial entities with novel mechanisms of action are clinically needed for treating resistant forms of tuberculosis. The purpose of this study was to evaluate anti-tubercular activity and selectivity of seven recently isolated natural products from Colombian plants.MICs were determined using a liquid medium growth inhibition assay for Mycobacterium tuberculosis H(37)Rv and both solid and liquid media growth inhibition assays for Mycobacterium bovis BCG. Escherichia coli growth inhibition and mammalian macrophage cell toxicity were evaluated to establish the degree of selectivity of the natural product against whole cell organisms. Enzymatic inhibition of ATP-dependent MurE ligase from M. tuberculosis was assayed using a colorimetric phosphate detection method. The most active compound, 3-methoxynordomesticine hydrochloride, was further investigated on M. bovis BCG for its inhibition of sigmoidal growth, acid-fast staining and viability counting analysis.Aporphine alkaloids were found to be potent inhibitors of slow-growing mycobacterial pathogens showing favourable selectivity and cytotoxicity. In terms of their endogenous action, the aporphine alkaloids were found inhibitory to M. tuberculosis ATP-dependent MurE ligase at micromolar concentrations. A significantly low MIC was detected for 3-methoxynordomesticine hydrochloride against both M. bovis BCG and M. tuberculosis H(37)Rv.Considering all the data, 3-methoxynordomesticine hydrochloride was found to be a potent anti-tubercular compound with a favourable specificity profile. The alkaloid showed MurE inhibition and is considered an initial hit for exploring related chemical space.