Flavonolignan and Flavone Inhibitors of a Staphylococcus aureus Multidrug Resistance Pump:  Structure−Activity Relationships

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-01, Vol.44 (2), p.261-268
Main Authors: GUZ, Nathan R., STERMITZ, Frank R., JOHNSON, Jeffrey B., BEESON, Teresa D., WILLEN, Seth, HSIANG, Jen-Fang, LEWIS, Kim
Format: Article
Language:English
Subjects:
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors
Biological and medical sciences
Cells, Cultured
Drug Resistance, Microbial
Drug Resistance, Multiple
flavones
Flavonoids - chemical synthesis
Flavonoids - chemistry
Flavonoids - pharmacology
flavonolignans
Lignans - chemical synthesis
Lignans - chemistry
Lignans - pharmacology
Magnetic Resonance Spectroscopy
Medical sciences
Microbial Sensitivity Tests
NorA protein
Pharmacology. Drug treatments
Staphylococcus aureus
Staphylococcus aureus - drug effects
Staphylococcus aureus - metabolism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0004190