这项新研究由伊利诺斯大学化学教授Eric Oldfield领导，发表于《美国国家科学院院刊（Proceedings of the National Academy of Sciences）》。
“新型抗生素的需求显然是巨大的”Oldfield说，“现在已经出现完全耐药的细菌。细菌是聪明的，能够适应并找到方法来绕过我们开发的药物。所以我们需要针对多个靶点进行攻击，这样它们就难以通过微弱的改变来逃避打击。”
研究人员的兴趣点在于找到能够破坏细菌能量生产线，在细菌中关闭细胞过程的化合物。这些被称为解偶联剂（uncouplers）的药物，已经被用于治疗寄生虫感染。受到氯法齐明（clofazimine，一种现在被用于治疗结核病的麻风病药物）的启发，研究人员基于化学结构搜索了已有或开发中的药物，以找到解偶联剂。
“我们发现很多FDA批准的分子确实可以杀死细菌，也可以作为解偶联剂。这让我们感到惊喜”Oldfield说，“更好的是，这些分子中有的还能够抑制特定的细菌酶，或者破坏细胞膜或细胞壁。”
这样的多靶点药物可能更广泛地应用于对抗各种感染。
例如，研究中发现的最有前途的解偶联剂之一是vacquinol，这种化合物正在开发用于治疗胶质母细胞瘤。他们发现，除了解偶联属性，vacquinol还能够抑制一种涉及结核菌毒性的关键酶。
研究人员随后寻找与vacquinol结构相似的其他化合物，并且发现这些化合物是能够对抗结核病和金黄色葡萄球菌的强效抗生素。
“这是一种新的抗菌方法，以酶和细菌能量生产为靶点”Oldfield说道。
接下来，Oldfield希望开发能够在细菌细胞内部代谢为解偶联剂的化合物，进一步减少与人类细胞的相互作用，并使细菌更难以产生耐药性。例如，某些胃灼热药物能够在细胞内代谢为对抗结核病的化合物。
“整个想法是，有可能某些FDA已经批准的化合物能够发挥作用。你可以筛选一百万种化学物质来找到一种新的化合物，但通常对其毒理学一无所知，或者，你可以从已知的化合物开始”Oldfield说，“一旦你开始制造衍生品，你必须证明它们是安全的。相对于钻进化学实验室去筛选未知化合物，从已经获批的药物着手而得到安全有效衍生品的机会更大。”
DOI:?10.1073/pnas.1521988112
Antiinfectives targeting enzymes and the proton motive force
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 ofMycobacterium 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 (～0.5–2 μg/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 ～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.