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Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1ß in Cellular and Animal Infection Models.
Everett, Martin J; Davies, David T; Leiris, Simon; Sprynski, Nicolas; Llanos, Agustina; Castandet, Jérôme M; Lozano, Clarisse; LaRock, Christopher N; LaRock, Doris L; Corsica, Giuseppina; Docquier, Jean-Denis; Pallin, Thomas D; Cridland, Andrew; Blench, Toby; Zalacain, Magdalena; Lemonnier, Marc.
Afiliação
  • Everett MJ; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Davies DT; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Leiris S; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Sprynski N; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Llanos A; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Castandet JM; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • Lozano C; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • LaRock CN; Department of Microbiology and Immunology, Rollins Research Center, 1510 Clifton Rd, Atlanta, Georgia 30322, United States.
  • LaRock DL; Department of Microbiology and Immunology, Rollins Research Center, 1510 Clifton Rd, Atlanta, Georgia 30322, United States.
  • Corsica G; Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, Italy.
  • Docquier JD; Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, Italy.
  • Pallin TD; Centre d'Ingénierie des Protéines - InBioS, University of Liège, Allée du six Août 11, 4000 Liège, Belgium.
  • Cridland A; Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K.
  • Blench T; Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K.
  • Zalacain M; Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K.
  • Lemonnier M; Antabio SAS, Biostep, 436 rue Pierre et Marie Curie, 31670 Labège, France.
ACS Infect Dis ; 9(2): 270-282, 2023 02 10.
Article em En | MEDLINE | ID: mdl-36669138
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-1ß. Furthermore, inhibition of LasB-mediated IL-1ß 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Fatores de Virulência Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Fatores de Virulência Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article