Nature communications · 2022
A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Roberts Kade D, Zhu Yan, Azad Mohammad A K, Han Mei-Ling, Wang Jiping, Wang Lynn, Yu Heidi H, Horne Andrew S, Pinson Jo-Anne, Rudd David, Voelcker Nicolas H, Patil Nitin A, Zhao Jinxin, Jiang Xukai, Lu Jing, Chen Ke, Lomovskaya Olga, Hecker Scott J, Thompson Philip E, Nation Roger L, Dudley Michael N, Griffith David C, Velkov Tony, Li Jian
Аннотация
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.