The development of fluconazole resistance in Candida albicans - an example of microevolution of a fungal pathogen.

Abstract

The yeast Candida albicans is a member of the microbiota in the gastrointestinal and urogenital tracts of most healthy persons, but it can also cause symptomatic infections, especially in immunocompromised patients. During the life-long association with its human host, C. albicans generates genetically altered variants that are better adapted to changes in their environment. A prime example of this microevolution is the development of resistance to the commonly used drug fluconazole, which inhibits ergosterol biosynthesis, during antimycotic therapy. Fluconazole resistance can be caused by mutations in the drug target, by changes in the sterol biosynthesis pathway, and by gain-of-function mutations in transcription factors that result in the constitutive upregulation of ergosterol biosynthesis genes and multidrug efflux pumps. Fluconazole also induces genomic rearrangements that result in gene amplification and loss of heterozygosity for resistance mutations, which further increases drug resistance. These genome alterations may affect extended chromosomal regions and have additional phenotypic consequences. A striking case is the loss of heterozygosity for the mating type locus MTL in many fluconazole-resistant clinical isolates, which allows the cells to switch to the mating-competent opaque phenotype. This, in turn, raises the possibility that sexual recombination between different variants of an originally clonal, drug-susceptible population may contribute to the generation of highly fluconazole-resistant strains with multiple resistance mechanisms. The gain-of-function mutations in transcription factors, which result in deregulated gene expression, also cause reduced fitness. In spite of this, many clinical isolates that contain such mutations do not exhibit fitness defects, indicating that they have overcome the costs of drug resistance with further evolution by still unknown mechanisms.