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

• Type of Material: Article
• Authors: Martin J. Everett, Biostep; David T. Davies, Biostep; Simon Leiris, Biostep; Nicolas Sprynski, Biostep; Agustina Llanos, Biostep; Jerome M Castandet, Biostep; Clarisse Lozano, Biostep; Christopher LaRock, Emory University; Doris L. LaRock, Emory University; Giuseppina Corsica, Università degli Studi di Siena; Jean-Denis Docquier, Università degli Studi di Siena; Thomas D. Pallin, Charles River UK Ltd.; Andrew Cridland, Charles River UK Ltd.; Toby Blench, Charles River UK Ltd.; Magdalena Zalacain, Biostep; Marc Lemonnier, Biostep
• Language: English
• Date: 2022-01-01
• Publisher: ACS
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by American Chemical Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/acsinfecdis.2c00418
• Title of Journal or Parent Work: ACS Infectious Diseases
• Volume: 9
• Issue: 2
• Start Page: 270
• End Page: 282
• Grant/Funding Information: Research reported in this publication is supported by CARB-X. CARB-X’s funding for this project is provided in part with federal funds from the U.S. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; under agreement number: 75A50122C00028, and by an award from Wellcome (WT224842). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of CARB-X or any of its funders.
• Keywords: Kinetics; LasB; IL-1β; elastase; Models, Animal; pseudolysin; Mice; Animals; antivirulence; Pseudomonas aeruginosa; Virulence Factors; Pancreatic Elastase
• Research Categories: Biology, Virology

Abstract

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.