A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens.
A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens.
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DOI：
10.1038/s41467-022-29234-3
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发表时间：
2022-03-25
影响因子：
16.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Roberts KD;Zhu Y;Azad MAK;Han ML;Wang J;Wang L;Yu HH;Horne AS;Pinson JA;Rudd D;Voelcker NH;Patil NA;Zhao J;Jiang X;Lu J;Chen K;Lomovskaya O;Hecker SJ;Thompson PE;Nation RL;Dudley MN;Griffith DC;Velkov T;Li J
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。旧的多粘菌素脂肽抗生素(多粘菌素B和粘菌素)通常是唯一的治疗选择，因为对所有其他类别的抗生素和瘦素抗生素药物开发流水线具有耐药性。然而，多粘菌素B和粘菌素在安全性(剂量限制性肾毒性、急性毒性)、药代动力学(肺部暴露不良)和有效性(抗肺部感染活性可忽略不计)方面存在重大问题，严重限制了它们的临床应用。在这里，我们利用化学生物学来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，开发出一种新的合成脂肽，在结构和药理上与多粘菌素B和粘菌素不同。这使得临床候选药物F365(QPX9003)对由最重要的耐多药铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌引起的肺部感染具有优越的安全性和有效性。多粘菌素通常是多药耐药(MDR)细菌的最后治疗选择，但安全性和有效性不佳。在这里，作者报告了一种合成脂肽的发现和开发，该脂肽对首要的耐多药革兰氏阴性病原体具有更好的安全性和有效性。
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. Polymyxins are often the last therapeutic option for multidrug-resistant (MDR) bacteria, but have suboptimal safety and efficacy. Here the authors report the discovery and development of a synthetic lipopeptide with an improved safety and efficacy against top-priority MDR Gram-negative pathogens.
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影响因子：
21.1
作者：
Nang SC;Azad MAK;Velkov T;Zhou QT;Li J
通讯作者：
Li J
影响因子：
4.9
作者：
Azad, Mohammad A. K.;Akter, Jesmin;Li, Jian
通讯作者：
Li, Jian
影响因子：
4.2
作者：
Eljaaly K;Bidell MR;Gandhi RG;Alshehri S;Enani MA;Al-Jedai A;Lee TC
通讯作者：
Lee TC
影响因子：
5.1
作者：
Galea, Charles A.;Han, Meiling;Velkov, Tony
通讯作者：
Velkov, Tony
影响因子：
5.2
作者：
Landersdorfer, Cornelia B.;Wang, Jiping;Nation, Roger L.
通讯作者：
Nation, Roger L.