2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain
2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain
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DOI：
10.1038/s41598-018-38064-7
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发表时间：
2019-02-06
影响因子：
4.6
通讯作者：
Obregon-Henao, Andres
中科院分区：
文献类型：
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作者：
Jeon, Albert Byungyun;Ackart, David F.;Obregon-Henao, Andres
迫切需要开发抗结核病的新药。特别是，以耐药结核分枝杆菌（M. tuberculosis）为目标至关重要，这在一定程度上造成了治疗所需的冗长的抗生素方案。我们先前假设结核分枝杆菌体内生物膜样群落的存在可能有助于这种药物耐受性。与这一假设相一致的是，在体外结核分枝杆菌生物膜模型中，某些具有抗生物膜活性的2-氨基咪唑（2-AIs）分子被证明可以恢复分枝杆菌的耐药性。在探索其作用机制时，偶然发现这些2-AI分子还通过影响分枝杆菌的蛋白分泌和脂质输出来增强β -内酰胺类抗生素。由于这两种细菌过程是能量依赖的，因此本文评估了2-AI化合物是否影响分枝杆菌的生物能量学。在低浓度下，铅2-AI化合物2B8，质子动力的两个组成部分都崩溃了，类似于其他阳离子两亲体。然而，有趣的是，2B8对结核分枝杆菌的最低抑制浓度与确定干扰分枝杆菌电子传递链的较高药物浓度相关。总的来说，本研究阐明了2-AIs对结核分枝杆菌的作用机制，为更好地了解分枝杆菌的生物能量学和开发具有更高抗分枝杆菌活性的化合物提供了工具。
There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of in vivo biofilm-like communities of M. tuberculosis could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an in vitro M. tuberculosis biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated beta-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against M. tuberculosis correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against M. tuberculosis, providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.