Title |
REVIEW] The development of fluconazole resistance in Candida albicans – an example of microevolution of a fungal pathogen |
Author |
Joachim Morschhäuser |
Address |
Institute for Molecular Infection Biology, University of Würzburg, D-97080 Würzburg, Germany |
Bibliography |
Journal of Microbiology, 54(3),192-201, 2016,
|
DOI |
10.1007/s12275-016-5628-4
|
Key Words |
drug resistance, fitness costs, gain-of-function
mutation, genome alterations, loss of heterozygosity |
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. |