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 ofSaccharomyces cerevisiae that conferred resistance to AbA when the gene was present in multiple copies. The gene was identical toYOR1/YRS1 , which confers resistance to oligomycin, reveromycin, and organic anions, none of which have structures similar to that of AbA. We also isolated anaur3 R recessive mutant ofS. cerevisiae with increased resistance to AbA. Northern hybridization showed that theaur3 R mutant expressed not onlyYOR1 but also the ABC transporter-encoding genePDR5 at high levels. Genetic studies showed that theaur3 R mutant had a mutation in thePDR1 gene, which encodes a transcriptional regulator ofPDR5 andYOR1 . Analysis of ayor1 disruptant of theaur3/pdr1 mutant showed that both the functionalYOR1 gene and the mutation inPDR1 were necessary for AbA resistance. These results suggest thatYOR1 is more important thanPDR5 for AbA resistance. We found inCandida albicans a novel gene whose sequence was similar to the sequence ofYOR1 inS. cerevisiae . The amino acid sequence of theC. albicans YOR1 homolog showed no significant similarity to the sequences ofCDR1 andCDR2 , which are ABC transporters ofC. albicans . Furthermore, AbA inhibited the efflux of the anticancer agent vincristine through P glycoproteins in cancer cells with multidrug resistance.