Molecular mechanisms underlying the emergence of polygenetic antifungal drug resistance in mismatch repair mutants of .

BACKGROUND

Fungal infections are common life-threatening diseases amongst immunodeficient individuals. Invasive fungal disease is commonly treated with an azole antifungal agent, resulting in selection pressure and the emergence of drug resistance. Antifungal resistance is associated with higher mortality rates and treatment failure, making the current clinical management of fungal disease very challenging. Clinical isolates from a variety of fungi have been shown to contain mutations in the gene, encoding a component of the DNA mismatch repair pathway. Mutation of results in an elevated mutation rate that can increase the opportunity for selectively advantageous mutations to occur, accelerating the development of antifungal resistance.

OBJECTIVES

To characterize the molecular mechanisms causing the microevolutionary emergence of antifungal resistance in mismatch repair mutants of .

METHODS

The mechanisms resulting in the emergence of antifungal resistance were investigated using WGS, characterization of deletion mutants and measuring ploidy changes.

RESULTS

The genomes of resistant strains did not possess mutations in or other genes of the ergosterol biosynthesis pathway. Antifungal resistance was due to small contributions from mutations in many genes. does not directly affect ploidy changes.

CONCLUSIONS

This study provides evidence that resistance to fluconazole can evolve independently of mutations. A common microevolutionary route to the emergence of antifungal resistance involves the accumulation of mutations that alter stress signalling, cellular efflux, membrane trafficking, epigenetic modification and aneuploidy. This complex pattern of microevolution highlights the significant challenges posed both to diagnosis and treatment of drug-resistant fungal pathogens.