title: Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance.
abstract: Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, 06123 Perugia, Italy. stefano.sabatini@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Francesca
authors.initials: F
authors.lastname: Gosetto
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Luca
authors.initials: L
authors.lastname: Sancineto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimovska
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D060326:Chemistry Techniques, Synthetic; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines; C541577:2-phenylquinoline; C075040:NorA protein, Staphylococcus