论文标题
开发抗菌化合物，阻止进化途径的抗性
Development of antibacterial compounds that block evolutionary pathways to resistance
论文作者
论文摘要
抗生素耐药性是全球挑战。阻止电阻的潜在方法是同时抑制靶细菌蛋白的WT和已知的逃生变体。在这里，我们应用了一种集成的计算和实验方法，以发现抑制大肠杆菌二氢叶酸大肠杆菌还原酶（DHFR）的WT和Trimethoprim（TMP）抗性突变体的化合物。我们确定了一种新型化合物（CD15-3），该化合物抑制WT DHFR及其TMP抗TMP变体L28R，P21L和A26T，具有IC50 50-75微孔针对WT和TMP抗性菌株。与TMP相比，在体外进化中，对CD15-3的抗性显着延迟。 CD15-3抗性菌株的整个基因组测序在靶基因基因座中没有突变。相反，几个外排泵的基因重复导致对CD15-3的抗性较弱（IC50的增加了双重）。总的来说，我们的结果证明了策略开发进化药物的希望 - 可以阻止病原体中进化逃生路线的化合物。
Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50-75 micromoles against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which block evolutionary escape routes in pathogens.
