Specific chromosome alterations in fluconazole-resistant mutants of Candida albicans

The exposure of Candida albicans to fluconazole resulted in the nondisjunct ion of two specific chromosomes in 17 drug-resistant mutants, each obtained by an independent mutational event, The chromosomal changes occurred at hi gh frequencies and were related to the duration of the drug exposure, The l oss of one homologue of chromosome 4 occurred after incubation on a flucona zole medium for 7 days. A second change, the gain of one copy of chromosome 3, was observed after exposure for 35 or 40 days. We found that the mRNA l evels of ERG11, CDR1, CDR2, and MDR1, the candidate fluconazole resistance genes, remained either the same or were diminished. The lack of overexpress ion of putative drug pumps or the drug target indicated that some other mec hanism(s) may be operating. The fluconazole resistance phenotype, electroph oretic karyotypes, and transcript levels of mutants were stable after growt h for 112 generations in the absence of fluconazole, This is the first repo rt to demonstrate that resistance to fluconazole can be dependent on chromo somal nondisjunction. Furthermore, we suggest that a low-level resistance t o fluconazole arising during the early stages of clinical treatment may occ ur by this mechanism. These results support our earlier hypothesis that cha nges in C. albicans chromosome number is a common means to control a resour ce of potentially beneficial genes that are related to important cellular f unctions.