N-caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors.
As part of an ongoing project to identify plant natural products as efflux pump inhibitors (EPIs), bioassay-guided fractionation of the methanolic extract of Mirabilis jalapa Linn. (Nyctaginaceae) led to the isolation of an active polyphenolic amide: N-trans-feruloyl 4'-O-methyldopamine. This compound showed moderate activity as an EPI against multidrug-resistant (MDR) Staphylococcus aureus overexpressing the multidrug efflux transporter NorA, causing an 8-fold reduction of norfloxacin MIC at 292 microM (100 microg/mL). This prompted us to synthesize derivatives in order to provide structure-activity relationships and to access more potent inhibitors. Among the synthetic compounds, some were more active than the natural compound and N-trans-3,4-O-dimethylcaffeoyl tryptamine showed potentiation of norfloxacin in MDR S. aureus comparable to that of the standard reserpine.
Michalet
Serge
S
DPM UMR 5063 CNRS-UJF, Equipe de Pharmacognosie, UFR de Pharmacie de Grenoble, Domaine de La Merci, 38706 La Tronche cedex, France. sergemichalet@yahoo.fr
Cartier
Gilbert
G
David
Bruno
B
Mariotte
Anne-Marie
AM
Dijoux-franca
Marie-Geneviève
MG
Kaatz
Glenn W
GW
Stavri
Michael
M
Gibbons
Simon
S
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002934:Cinnamates / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004996:Ethidium; D026901:Membrane Transport Proteins / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D039282:Mirabilis / Q000378:metabolism*; D009643:Norfloxacin / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000900:Anti-Bacterial Agents; D002109:Caffeic Acids; D002934:Cinnamates; D026901:Membrane Transport Proteins; D010936:Plant Extracts; D012110:Reserpine; D004996:Ethidium; D009643:Norfloxacin