title: Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: structure-activity relationships.
abstract: Although some progress has been reported on structure-activity relationships (SARs) for inhibitors of mammalian P-glycoprotein MDR efflux pumps, there is almost nothing in the literature regarding SARs for inhibitors of any bacterial efflux pump. Indeed, only a few of these have been described. Our discovery of a potent naturally occurring flavonolignan inhibitor of the NorA MDR pump of Staphylococcus aureus provided a structural foundation upon which SARs could be assessed via synthetic analogues. Several flavonolignans were prepared which proved to have greater potency than the natural isolate, 5'-methoxyhydnocarpin-D, while others showed decreased potency. Surprisingly, some simple alkylated flavones also were quite active MDR pump inhibitors. Variability of activity among the compounds tested was sufficient so that at least some SARs could be postulated and compared with those known for P-glycoprotein.
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Guz
authors.forename: F R
authors.initials: FR
authors.lastname: Stermitz
authors.forename: J B
authors.initials: JB
authors.lastname: Johnson
authors.forename: T D
authors.initials: TD
authors.lastname: Beeson
authors.forename: S
authors.initials: S
authors.lastname: Willen
authors.forename: J
authors.initials: J
authors.lastname: Hsiang
authors.forename: K
authors.initials: K
authors.lastname: Lewis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017705:Lignans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids; D017705:Lignans