title: From 6-aminoquinolone antibacterials to 6-amino-7-thiopyranopyridinylquinolone ethyl esters as inhibitors of Staphylococcus aureus multidrug efflux pumps.
abstract: The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, 06123 Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimovska
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Brincat
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004952:Esters / Q000737:chemistry*; D004996:Ethidium / Q000494:pharmacology; D019450:Genes, MDR / Q000235:genetics; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D004952:Esters; C032928:6-aminoquinoline; D004996:Ethidium