铜绿假单胞菌
微生物学
体内
弹性蛋白酶
左氧氟沙星
抗生素
体外
病菌
离体
生物
医学
免疫学
细菌
酶
生物化学
生物技术
遗传学
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 Brandstetter,Rolf W. Hartmann,Christian Ducho,Claus‐Michael Lehr,Christoph Beißwenger,Rolf‐Joachim Müller,Katharina Rox,Jörg Haupenthal,Anna K. H. Hirsch
标识
DOI:10.26434/chemrxiv-2023-bszcb
摘要
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 non-traditional 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 co-crystal 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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