Inhibitors of the Elastase LasB for the Treatment of <i>Pseudomonas aeruginosa</i> Lung Infections

Abstract

Infections caused by the Gram-negative pathogen <i>Pseudomonas aeruginosa</i> 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 <i>P. aeruginosa</i>-derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding <i>in vitro</i> ADMET and PK profile, auspicious activity both <i>in vitro</i> and <i>in vivo</i>. We established the mode of action through a cocrystal structure of our lead compound with LasB and in several <i>in vitro</i> and <i>ex vivo</i> 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.