title: Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance.
abstract: Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Maura
authors.affiliation: Institute for Molecular Microbiology and Biotechnology, University of Münster , 48149 Münster, Germany.
authors.forename: Steffen L
authors.initials: SL
authors.lastname: Drees
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Arunava
authors.initials: A
authors.lastname: Bandyopadhaya
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kitao
authors.affiliation: Aptuit, 37135 Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Negri
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Starkey
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Biliana
authors.initials: B
authors.lastname: Lesic
authors.affiliation: INRS Institut Armand Frappier , Laval, Quebec H7V 1B7, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Milot
authors.affiliation: INRS Institut Armand Frappier , Laval, Quebec H7V 1B7, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Déziel
authors.affiliation: Spero Therapeutics, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.affiliation: Spero Therapeutics, Cambridge, Massachusetts 02139, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Pucci
authors.affiliation: Aptuit, 37135 Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felici
authors.affiliation: Institute for Molecular Microbiology and Biotechnology, University of Münster , 48149 Münster, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fetzner
authors.affiliation: INRS Institut Armand Frappier , Laval, Quebec H7V 1B7, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Lépine
authors.affiliation: Shriners Hospitals for Children Boston , Boston, Massachusetts 02114, United States.
authors.forename: Laurence G
authors.identifier: 0000-0002-5374-4332
authors.initials: LG
authors.lastname: Rahme
mesh_terms: D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods; D064798:Polypharmacology; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000235:genetics*; D018085:Regulon / Q000187:drug effects*; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors
chemical_list: D004791:Enzyme Inhibitors; D037521:Virulence Factors