Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections.

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 pathobloc

SUBMITTER: Konstantinovic J 

PROVIDER: S-EPMC10755728 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature