Azole resistance mechanisms in pathogenic M. furfur.

ABSTRACT

Malassezia are emerging fungal pathogens causing opportunistic skin and severe systemic infection. Nosocomial outbreaks are associated with azole resistance and understanding of the underlying mechanisms are limited to knowledge from other fungal species. Herein, we identified distinct antifungal susceptibility patterns in 26 Malassezia furfur isolates derived from healthy and diseased individuals. A Y67F CYP51 mutation was identified in five isolates of M. furfur However, this mutation alone was insufficient to induce reduce azole susceptibility in the wild type strain. RNA-seq and differential gene analysis of healthy and disease derived strains exposed to clotrimazole in vitro identified several key metabolic pathways and transporter proteins which are involved in reduce azole susceptibility. The pleiotropic drug transporter PDR10 was the single most highly upregulated transporter gene in multiple strains of M. furfur after azole treatment and increased expression of PDR10 is associated with reduced azole susceptibility in some systemic disease isolates of M. furfur Deletion of PDR10 in a pathogenic M. furfur strain with reduced susceptibility reduced MIC values to the level of that in susceptible isolates. The current dearth of antifungal technologies, globally emerging multi-azole resistance, and broad agriculture and consumer care use of azoles means improved understanding of the mechanisms underlying intrinsic and acquired azole resistance in Malassezia is crucial for development of antibiotic stewardship and antifungal treatment strategies.