Antiinfectives targeting enzymes and the proton motive force
Antiinfectives targeting enzymes and the proton motive force
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DOI：
10.1073/pnas.1521988112
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发表时间：
2015-12-22
影响因子：
11.1
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Feng, Xinxin;Zhu, Wei;Oldfield, Eric
对新型抗生素的需求不断增长。以质子动力（PMF）为目标的化合物（解偶联剂）代表了一类可能被开发的化合物，因为它们已经用于治疗寄生虫感染，并且人们对它们用于治疗其他疾病（例如糖尿病）感兴趣。在这里，我们测试了一系列化合物的解偶联剂活性，其中大多数具有已知的抗感染活性。许多阳离子两亲物检测呈阳性，并且一些靶向类异戊二烯生物合成或影响脂质双层结构。例如，我们发现克罗米芬是一种解偶联剂，它是最近发现的一种十一异戊二烯二磷酸合酶抑制剂，对金黄色葡萄球菌具有活性。通过计算机筛选，我们发现抗多形性胶质母细胞瘤药物先导剂 vacquinol 是结核分枝杆菌结核菌素腺苷合酶的抑制剂，也是解偶联剂。由于痘喹诺也是结核分枝杆菌细胞生长的抑制剂，因此我们使用基于痘痘诺结构的相似性搜索，找到了对结核分枝杆菌和金黄色葡萄球菌具有有效（类似于 0.5-2 μg/mL）活性的类似物。我们的结果对通过表型筛选和基因组测序发现的大多数新的结核病药物先导物是具有膜靶标的高度亲脂性（logP类似于5.7）碱基的观察结果给出了逻辑解释，因为除了破坏PMF之外，预计这些物质会分配到疏水性膜中，抑制膜蛋白。这种多重靶向预计对于克服耐药性的发展具有重要意义，因为预计靶向膜的物理特性不易受到耐药性发展的影响。
There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (similar to 0.5-2 mu g/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP similar to 5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.