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

Vijay K. Singh, Marianna Almpani, Damien Maura, Tomoe Kitao, Livia Ferrari, Stefano Fontana, Gabriella Bergamini, Elisa Calcaterra, Chiara Pignaffo, Michele Negri, Thays Oliveira Pereira, Frances Skinner, Manos Gkikas, Danielle Andreotti, Antonio Felici, Eric Déziel, Francois Lépine and Laurence G. Rahme ()
Additional contact information
Vijay K. Singh: Harvard Medical School and Massachusetts General Hospital
Marianna Almpani: Harvard Medical School and Massachusetts General Hospital
Damien Maura: Harvard Medical School and Massachusetts General Hospital
Tomoe Kitao: Harvard Medical School and Massachusetts General Hospital
Livia Ferrari: Aptuit (Verona) S.rl, an Evotec Company
Stefano Fontana: Aptuit (Verona) S.rl, an Evotec Company
Gabriella Bergamini: Aptuit (Verona) S.rl, an Evotec Company
Elisa Calcaterra: Aptuit (Verona) S.rl, an Evotec Company
Chiara Pignaffo: Aptuit (Verona) S.rl, an Evotec Company
Michele Negri: In vitro Chemotherapy Laboratory, Aptuit (Verona) S.r.l., an Evotec Company
Thays Oliveira Pereira: Institut National de la Recherche Scientifique (INRS), Laval
Frances Skinner: University of Massachusetts Lowell
Manos Gkikas: University of Massachusetts Lowell
Danielle Andreotti: Aptuit (Verona) S.r.l., an Evotec Company
Antonio Felici: In Vitro Biology, Aptuit (Verona) S.r.l., an Evotec Company
Eric Déziel: Institut National de la Recherche Scientifique (INRS), Laval
Francois Lépine: Institut National de la Recherche Scientifique (INRS), Laval
Laurence G. Rahme: Harvard Medical School and Massachusetts General Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32833-9

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