The Microevolution of Antifungal Drug Resistance in Pathogenic Fungi

Abstract

The mortality rates of invasive fungal infections remain high because of the limited number of antifungal drugs available and antifungal drug resistance, which can rapidly evolve during treatment. Mutations in key resistance genes such as ERG11 were postulated to be the predominant cause of antifungal drug resistance in the clinic. However, recent advances in whole genome sequencing have revealed that there are multiple mechanisms leading to the microevolution of resistance. In many fungal species, resistance can emerge through ERG11-independent mechanisms and through the accumulation of mutations in many genes to generate a polygenic resistance phenotype. In addition, genome sequencing has revealed that full or partial aneuploidy commonly occurs in clinical or microevolved in vitro isolates to confer antifungal resistance. This review will provide an overview of the mutations known to be selected during the adaptive microevolution of antifungal drug resistance and focus on how recent advances in genome sequencing technology have enhanced our understanding of this process.

Keywords: adaptation; aneuploidy; antifungal drugs; fungi; microevolution; mutator; pathogen; phenotypic diversity; ploidy; resistance.

Figure 1

Adaptive evolution of antifungal resistance. (A). Cells in the population that possess a mutation resulting in antifungal drug resistance are selected and become predominant in the population. (B). An elevated mutation rate provides higher genetic diversity within a population on which selection for antifungal-resistant cells can occur. (C). Transient aneuploidy (heteroresistance) occurs in the presence of an antifungal to confer resistance. (D). Permanent aneuploidy-conferring antifungal resistance is selected for in a clinical population. The thick black lines represent schematic chromosomes, with white lines representing mutations.

Figure 2

Molecular mechanisms of resistance to antifungal drugs. Schematic of the fungal cell membrane and wall showing the mechanism of action of the five antifungals and the mechanisms of resistance (5FC: 5-fluorocytosine and 5FU: 5-fluorouracil). Mechanisms common to several different fungal species are indicated in red (text, arrows or boxes), those specific to A. fumigatus in blue (text and boxes), to C. neoformans in purple text and to Candida species in green text. The fungal cell wall comprises chitin (blue), ß-1,3-glucan (light green), ß1,6- glucan (orange), proteins (yellow), α-1,3-glucan (red) and galactomannans (brown). Transcription factors and proteins that regulate ergosterol biosynthesis are shown in yellow and orange, respectively. Damage Resistance Protein 1 (Dap1) complex is shown in green.