Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary.
University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
PLoS Biol. 2020 Oct 5;18(10):e3000819. doi: 10.1371/journal.pbio.3000819. eCollection 2020 Oct.
Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections.
抑制多个细菌靶标的抗生素为应对耐药性进化提供了一种有前途的治疗策略，但开发此类抗生素具有挑战性。在这里，我们通过使用药物化学工作流程证明了平衡多靶向抗生素的合理设计是可行的。由此产生的先导化合物 ULD1 和 ULD2 属于一种新的化学类别，几乎等效力地抑制细菌 DNA 回旋酶和拓扑异构酶 IV 复合物，并与靶蛋白 ATP 结合口袋中的多个进化保守氨基酸相互作用。ULD1 和 ULD2 对广泛的革兰氏阳性菌具有极好的效力。值得注意的是，这些化合物的功效针对广泛的多药耐药性金黄色葡萄球菌临床株进行了测试。针对葡萄球菌感染具有临床相关性的抗生素未能抑制这些分离株的很大一部分，而 ULD1 和 ULD2 均能抑制所有这些分离株（最低抑菌浓度 [MIC]≤1μg/mL）。针对这些化合物的耐药性突变很少见，对化合物敏感性的影响有限，但会大大降低细菌生长。基于它们在小鼠感染模型中表现出的功效和缺乏毒性，这些化合物可能会转化为针对多药耐药性细菌感染的新疗法。
