Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models

• DOI: 10.1021/acsinfecdis.2c00418
• Publication Date: 2023-01-20T20:57:21Z
• Authors: Martin J. Everett; David T. Davies; Simon Leiris; Nicolas Sprynski; Agustina Llanos; Jérôme M. Castandet; Clarisse Lozano; Christopher N. La...; Doris L. LaRock; Giuseppina Corsica; Jean-Denis Docquier; Thomas D. Pallin; Andrew Cridland; Toby Blench; Magdalena Zalacain; Marc Lemonnier
• Keywords: 0301 basic medicine; Pancreatic Elastase; Virulence Factors; IL-1β; LasB; Pseudomonas aeruginosa; antivirulence; elastase; pseudolysin; pseudolysin; Mice; Kinetics; 03 medical and health sciences; IL-1β; Models, Animal; Pseudomonas aeruginosa; antivirulence; elastase; Animals; LasB

LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1β. Furthermore, inhibition of LasB-mediated IL-1β activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen.