Inhibitory effects of gallic acid ester derivatives on Saccharomyces cerevisiae multidrug resistance protein Pdr5p.
Overexpression of the Saccharomyces cerevisiae ABC transporter Pdr5p confers resistance to a range of structurally unrelated xenobiotics. This property allows Pdr5p to be used as a target for novel multidrug resistance reversal reagents or chemosensitizers. Herein, we report the effects of gallic acid derivatives with substitutions either on the ester moiety or in the benzene ring on the activity of Pdr5p. Compounds with a longer side chain (8-16 carbons) resulted in greater inhibition of Pdr5p ATPase. Derivatives with side chains of 8-12 carbons that retained hydroxyl groups on the benzene ring extensively inhibited Pdr5p ATPase activity. These compounds almost completely inhibited the efflux of the Pdr5p fluorescent substrate Rhodamine 6G and at 25 muM chemosensitized the Pdr5p-overexpressing strain AD124567 to fluconazole (0.4 mg mL(-1)). Gallic acid derivatives may be a new class of Pdr5p inhibitors.
Pereira Rangel
Luciana
L
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral/IMPPG, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Fritzen
Márcio
M
Yunes
Rosendo Augusto
RA
Leal
Paulo César
PC
Creczynski-Pasa
Tânia Beatriz
TB
Ferreira-Pereira
Antônio
A
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000935:Antifungal Agents / Q000378:metabolism*; D026141:Drug Resistance, Multiple, Fungal / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012235:Rhodamines / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; C092438:PDR5 protein, S cerevisiae; D012235:Rhodamines; D029701:Saccharomyces cerevisiae Proteins; C026188:rhodamine 6G; D005707:Gallic Acid; D000251:Adenosine Triphosphatases