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Tackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy.
Singh, Vijay K; Almpani, Marianna; Maura, Damien; Kitao, Tomoe; Ferrari, Livia; Fontana, Stefano; Bergamini, Gabriella; Calcaterra, Elisa; Pignaffo, Chiara; Negri, Michele; de Oliveira Pereira, Thays; Skinner, Frances; Gkikas, Manos; Andreotti, Danielle; Felici, Antonio; Déziel, Eric; Lépine, Francois; Rahme, Laurence G.
Afiliación
  • Singh VK; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Almpani M; Shriners Hospitals for Children, Boston, MA, 02114, USA.
  • Maura D; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.
  • Kitao T; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Ferrari L; Shriners Hospitals for Children, Boston, MA, 02114, USA.
  • Fontana S; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.
  • Bergamini G; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Calcaterra E; Shriners Hospitals for Children, Boston, MA, 02114, USA.
  • Pignaffo C; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.
  • Negri M; Voyager Therapeutics, Cambridge, MA, 02139, USA.
  • de Oliveira Pereira T; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Skinner F; Shriners Hospitals for Children, Boston, MA, 02114, USA.
  • Gkikas M; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.
  • Andreotti D; T. Kitao, Department of Microbiology, Graduate School of Medicine, Gifu University, Gifu, 501-1194, Japan.
  • Felici A; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy.
  • Déziel E; DMPK Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy.
  • Lépine F; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy.
  • Rahme LG; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy.
Nat Commun ; 13(1): 5103, 2022 08 30.
Article en En | MEDLINE | ID: mdl-36042245
Intestinal barrier derangement allows intestinal bacteria and their products to translocate to the systemic circulation. Pseudomonas aeruginosa (PA) superimposed infection in critically ill patients increases gut permeability and leads to gut-driven sepsis. PA infections are challenging due to multi-drug resistance (MDR), biofilms, and/or antibiotic tolerance. Inhibition of the quorum-sensing transcriptional regulator MvfR(PqsR) is a desirable anti-PA anti-virulence strategy as MvfR controls multiple acute and chronic virulence functions. Here we show that MvfR promotes intestinal permeability and report potent anti-MvfR compounds, the N-Aryl Malonamides (NAMs), resulting from extensive structure-activity-relationship studies and thorough assessment of the inhibition of MvfR-controlled virulence functions. This class of anti-virulence non-native ligand-based agents has a half-maximal inhibitory concentration in the nanomolar range and strong target engagement. Using a NAM lead in monotherapy protects murine intestinal barrier function, abolishes MvfR-regulated small molecules, ameliorates bacterial dissemination, and lowers inflammatory cytokines. This study demonstrates the importance of MvfR in PA-driven intestinal permeability. It underscores the utility of anti-MvfR agents in maintaining gut mucosal integrity, which should be part of any successful strategy to prevent/treat PA infections and associated gut-derived sepsis in critical illness settings. NAMs provide for the development of crucial preventive/therapeutic monotherapy options against untreatable MDR PA infections.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones por Pseudomonas / Sepsis Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones por Pseudomonas / Sepsis Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido