Chromosome 1 trisomy confers resistance to aureobasidin A in Candida albicans

Introduction: Candida albicans is a prevalent opportunistic human Fungal pathogen. However, there are currently very few Antifungal treatments available. Inositol phosphoryl ceramide synthase is an essential and fungal-specific protein that also provides a novel and promising Antifungal target. Aureobasidin A is a widely used inhibitor of inositol phosphoryl ceramide synthase, however the mechanism of resistance to aureobasidin A is largely unknown in pathogenic fungi.

Methods: Here we investigated how C. albicans adapted to low and high concentrations of aureobasidin A.

Results and discussions: We identified trisomy of chromosome 1 as the predominant mechanism of rapid adaptation. Resistance to aureobasidin A was unstable because of the inherent instability of aneuploids. Importantly, chromosome 1 trisomy simultaneously regulated genes which were associated with aureobasidin A resistance that are on this aneuploid chromosome as well as on other chromosomes. Furthermore, the pleiotropic effect of aneuploidy caused altered resistance not only to aureobasidin A but also to other Antifungal drugs including caspofungin and 5-flucytosine. We posit aneuploidy provides a rapid and reversible mechanism of development of drug resistance and cross resistance in C. albicans.

Candida albicans; aneuploidy; antifungal drugs; aureobasidin A; sphingolipid biosynthesis.