Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens.

中文翻译：

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迭代方法指导 FabI 抑制剂法比霉素的发现，法比霉素是一种后期候选抗生素，具有体内抗耐药革兰氏阴性菌感染的功效


对渗透性缺陷菌株的基因组研究和实验揭示了多种可以杀死革兰氏阴性菌的生物靶标。然而，这些病原体强大的外膜和混杂的外排泵阻止了许多候选抗生素达到这些目标。其中一个有希望的目标是 FabI 酶，它催化细菌脂肪酸生物合成中的速率决定步骤。值得注意的是，FabI 抑制剂已进入针对金黄色葡萄球菌感染的临床试验，但尚未进入针对革兰氏阴性菌引起的感染的临床试验。在这里，我们合成了一套 FabI 抑制剂，其结构符合革兰氏阴性细菌的渗透规则，并利用针对具有挑战性的革兰氏阴性临床分离株的活性作为进步的过滤器。这种名为法比霉素的化合物对超过 200 种临床分离的大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌具有令人印象深刻的活性，并且不会杀死共生细菌。法比霉素与 FabI 复合物的 X 射线结构提供了对抑制作用的分子见解。法比霉素在革兰氏阴性菌引起的多种小鼠感染模型中表现出活性，包括具有挑战性的尿路感染模型。法比霉素具有转化前景，它的发现提供了额外的证据，证明抗生素可以被系统地修饰以在革兰氏阴性细菌中积累并杀死这些有问题的病原体。