Tackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy.

Autor: Singh VK; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.; Shriners Hospitals for Children, Boston, MA, 02114, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA., Almpani M; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.; Shriners Hospitals for Children, Boston, MA, 02114, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA., Maura D; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.; Shriners Hospitals for Children, Boston, MA, 02114, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.; Voyager Therapeutics, Cambridge, MA, 02139, USA., Kitao T; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.; Shriners Hospitals for Children, Boston, MA, 02114, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA.; T. Kitao, Department of Microbiology, Graduate School of Medicine, Gifu University, Gifu, 501-1194, Japan., Ferrari L; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Fontana S; DMPK Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Bergamini G; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Calcaterra E; Translational Biology Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Pignaffo C; DMPK Department, Aptuit (Verona) S.rl, an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Negri M; In vitro Chemotherapy Laboratory, Aptuit (Verona) S.r.l., an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., de Oliveira Pereira T; Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), Laval, Quebec, H7V 1B7, Canada., Skinner F; Department of Chemistry, University of Massachusetts Lowell, Lowell, MA, 01854, USA., Gkikas M; Department of Chemistry, University of Massachusetts Lowell, Lowell, MA, 01854, USA., Andreotti D; Global Synthetic Chemistry Department, Aptuit (Verona) S.r.l., an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy., Felici A; Department of Microbiology Discovery, In Vitro Biology, Aptuit (Verona) S.r.l., an Evotec Company, 37135 Via A. Fleming 4, Verona, Italy.; A Felici, Academic Partnership, Evotec SE, 37135 Via A. Fleming 4, Verona, Italy., Déziel E; Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), Laval, Quebec, H7V 1B7, Canada., Lépine F; Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), Laval, Quebec, H7V 1B7, Canada., Rahme LG; Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA. rahme@molbio.mgh.harvard.edu.; Shriners Hospitals for Children, Boston, MA, 02114, USA. rahme@molbio.mgh.harvard.edu.; Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA. rahme@molbio.mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 30; Vol. 13 (1), pp. 5103. Date of Electronic Publication: 2022 Aug 30.
DOI: 10.1038/s41467-022-32833-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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