title: Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus.
abstract: Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Brincat
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
authors.forename: Jose L
authors.initials: JL
authors.lastname: Raygada
authors.forename: Diixa
authors.initials: D
authors.lastname: Patel
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D016208:Databases, Factual; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004996:Ethidium / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D002939:Ciprofloxacin; D004996:Ethidium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010647:Phenyl Ethers; D011412:Propanolamines; D013449:Sulfonamides; C075040:NorA protein, Staphylococcus