Role of ABC transporters in aureobasidin A resistance.
Aureobasidin A (AbA) has strong antifungal effects arising from an unusual mechanism. We show that AbA interacts with ATP-binding cassette (ABC) transporters in yeast and mammalian cells. We isolated a gene of Saccharomyces cerevisiae that conferred resistance to AbA when the gene was present in multiple copies. The gene was identical to YOR1/YRS1, which confers resistance to oligomycin, reveromycin, and organic anions, none of which have structures similar to that of AbA. We also isolated an aur3R recessive mutant of S. cerevisiae with increased resistance to AbA. Northern hybridization showed that the aur3R mutant expressed not only YOR1 but also the ABC transporter-encoding gene PDR5 at high levels. Genetic studies showed that the aur3R mutant had a mutation in the PDR1 gene, which encodes a transcriptional regulator of PDR5 and YOR1. Analysis of a yor1 disruptant of the aur3/pdr1 mutant showed that both the functional YOR1 gene and the mutation in PDR1 were necessary for AbA resistance. These results suggest that YOR1 is more important than PDR5 for AbA resistance. We found in Candida albicans a novel gene whose sequence was similar to the sequence of YOR1 in S. cerevisiae. The amino acid sequence of the C. albicans YOR1 homolog showed no significant similarity to the sequences of CDR1 and CDR2, which are ABC transporters of C. albicans. Furthermore, AbA inhibited the efflux of the anticancer agent vincristine through P glycoproteins in cancer cells with multidrug resistance.
Ogawa
A
A
Biotechnology Research Laboratories, Takara Shuzo Co., Ltd., Otsu, Shiga, Japan.
Hashida-Okado
T
T
Endo
M
M
Yoshioka
H
H
Tsuruo
T
T
Takesako
K
K
Kato
I
I
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism; D001483:Base Sequence; D015152:Blotting, Northern; D003001:Cloning, Molecular; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D047630:Depsipeptides; D004352:Drug Resistance, Microbial / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D005800:Genes, Fungal / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D010456:Peptides, Cyclic / Q000494:pharmacology; D012331:RNA, Fungal / Q000737:chemistry / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D004271:DNA, Fungal; D047630:Depsipeptides; D010456:Peptides, Cyclic; D012331:RNA, Fungal; C071398:aureobasidin A; D014750:Vincristine