弹性蛋白酶 LasB 抑制剂治疗铜绿假单胞菌肺部感染
Inhibitors of the Elastase LasB for the Treatment ofPseudomonas aeruginosaLung Infections
作者:Jelena Konstantinović;Andreas M. Kany;Alaa Alhayek;Ahmed S. Abdelsamie;Asfandyar Sikandar;Katrin Voos;Yiwen Yao;Anastasia Andreas;Roya Shafiei;Brigitta Loretz;Esther Schönauer;Robert Bals;Hans Brandst
DOI:https://doi.org/10.1021/acscentsci.3c01102
发表时间:2023年
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摘要
由革兰氏阴性病原体铜绿假单胞菌引起的感染正在全球范围内出现,成为对人类健康的主要威胁。传统的抗生素单一疗法会迅速产生耐药性,这凸显了对新治疗概念的迫切需要。在此,我们报告了一种非传统方法,通过针对铜绿假单胞菌的主要毒力因子弹性蛋白酶 LasB 来对抗铜绿假单胞菌衍生的感染。我们发现了一种新的化学类别的膦酸盐,具有出色的体外 ADMET 和 PK 特性,在体外和体内均具有良好的活性。我们通过先导化合物与 LasB 的共晶结构以及在几个体外和离体模型中建立了作用模式。在小鼠中性粒细胞减少性肺部感染模型中,我们的病理阻滞剂与左氧氟沙星联合使用的概念证明以及血液中 LasB 蛋白水平的降低作为靶标参与的证明,证明了作为人类肺部感染辅助治疗的巨大潜力。
Abstract
Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat P. aeruginosa-derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding in vitro ADMET and PK profile, auspicious activity both in vitro and in vivo. We established the mode of action through a cocrystal structure of our lead compound with LasB and in several in vitro and ex vivo models. The proof of concept of a combination of our pathoblocker with levofloxacin in a murine neutropenic lung infection model and the reduction of LasB protein levels in blood as a proof of target engagement demonstrate the great potential for use as an adjunctive treatment of lung infections in humans.
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