Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Melbourne, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Nat Commun. 2022 Mar 25;13(1):1625. doi: 10.1038/s41467-022-29234-3.
The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.
多药耐药（MDR）革兰氏阴性病原体的出现是一个紧迫的全球医学挑战。由于对所有其他类别的抗生素的耐药性以及抗生素药物开发管道的匮乏，老的多粘菌素脂肽类抗生素（多粘菌素 B 和粘菌素）往往是唯一的治疗选择。然而，多粘菌素 B 和粘菌素在安全性（剂量限制的肾毒性、急性毒性）、药代动力学（肺部暴露不佳）和疗效（对肺部感染的作用可忽略不计）方面存在重大问题，这严重限制了它们的临床应用。在这里，我们采用化学生物学方法系统地优化多粘菌素支架中的多个非保守位置，并成功地将治疗效果与毒性分离，开发出一种新型的合成脂肽，其结构和药理学与多粘菌素 B 和粘菌素截然不同。这导致了临床候选药物 F365（QPX9003）的出现，它在治疗由优先 MDR 病原体铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌引起的肺部感染方面具有更好的安全性和疗效。
