title: From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump.
abstract: Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, 06123 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Rossolini
authors.forename: David
authors.initials: D
authors.lastname: Brandini
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010640:Phenothiazines; D013843:Thiazines; C075040:NorA protein, Staphylococcus; C031637:phenothiazine