Aureobasidin A, an antifungal cyclic depsipeptide antibiotic, is a substrate for both human MDR1 and MDR2/P-glycoproteins.
The human MDR1 gene encodes the multidrug transporter P-glycoprotein (Pgp). Although the MDR2/Pgp shares about 80% identity at the amino acid level with the MDR1/Pgp, the MDR2/Pgp cannot act as a multidrug transporter. We examined the drug sensitivity of Saccharomyces cerevisiae expressing either the human MDR1/Pgp or MDR2/ Pgp. The human MDR1/Pgp conferred about 4-fold resistance to aureobasidin A, a cyclic depsipeptide antifungal antibiotic, on the drug-sensitive yeast strains. Interestingly the human MDR2/Pgp also conferred about 2.5-fold resistance to aureobasidin A. The resistance to aureobasidin A conferred by the MDR2/Pgp as well as by the MDR1/Pgp was overcome by vinblastine, verapamil, and cyclosporin A, depending on their concentrations, but not by colchicine. Aureobasidin A probably interacts directly with Pgps, because it overcame multidrug resistance of human cells and inhibited azidopine photoaffinity labeling of MDR1/Pgp in human cell membranes. These results suggest the possibility that the human MDR1 and MDR2/Pgps have conserved domain(s) for drug recognition.
Kino
K
K
Laboratory of Biochemistry, Department of Agricultural Chemistry, Kyoto University, Japan.
Taguchi
Y
Y
Yamada
K
K
Komano
T
T
Ueda
K
K
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D000935:Antifungal Agents / Q000378:metabolism*; D047630:Depsipeptides; D018432:Drug Resistance, Multiple; D006801:Humans; D010456:Peptides, Cyclic / Q000378:metabolism; D011485:Protein Binding
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C071398:aureobasidin A; C095122:multidrug resistance protein 3