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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.

Adaptation to the changing environmental conditions experienced within a host requires genetic diversity within a microbial population. Genetic diversity arises from mutations which occur due to DNA damage from exposure to exogenous environmental stresses or generated endogenously through respiration or DNA replication errors. As mutations can be deleterious, a delicate balance must be obtained between generating enough mutations for micro-evolution to occur while maintaining fitness and genomic integrity. Pathogenic microorganisms can actively modify their mutation rate to enhance adaptive micro-evolution by increasing expression of error-prone DNA polymerases or by mutating or decreasing expression of genes required for DNA repair. Strains which exhibit an elevated mutation rate are termed mutators. Mutators are found in varying prevalence in clinical populations where large-effect beneficial mutations enhance survival and are predominately caused by defects in the DNA mismatch repair (MMR) pathway. Mutators can facilitate the emergence of antibiotic resistance, allow phenotypic modifications to prevent recognition and destruction by the host immune system and enable switching to metabolic and cellular morphologies better able to survive in the given environment. This review will focus on recent advances in understanding the phenotypic and genotypic changes occurring in MMR mutators in both prokaryotic and eukaryotic pathogens.