Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the firstin totochemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strainsin vitro, octapeptin C4 displayed poorin vivoefficacy, most likely due to high plasma protein binding. Nuclear magnetic resonance solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively drug-resistant (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria.In vivoefficacy was demonstrated in a murine bacteremia model with a colistin-resistantP. aeruginosaclinical isolate.

中文翻译：

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具有抗广泛耐药革兰氏阴性细菌作用的八肽素抗生素的结构，功能和生物合成来源

现在，对最后一种抗生素大肠菌素的耐药性已经广泛传播，迫切需要新的疗法。我们报道了八肽素的首创的totototochemical合成和临床前评价，八肽是一类与大肠菌素结构相关的脂肽。八肽素生物合成簇由三个非核糖体肽合成酶（OctA，OctB和OctC）组成，可产生两亲性抗生素八肽素C4，该肽可与膜结合并使其去极化。虽然八肽素C4在体外对耐多药（MDR）菌株具有活性，但其体内功效较差，这很可能是由于血浆蛋白的高结合力所致。核磁共振溶液结构，经验结构活性和结构毒性模型用于设计对MDR和广泛耐药性（XDR）细菌具有活性的合成八肽。然后将支架微妙地改变以减少血浆蛋白结合，同时保持抗MDR和XDR细菌的活性。在具有大肠菌素抗性P的鼠菌血症模型中证明了体内效力。铜绿细菌分离株。