Abstract
Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicans Candida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.
Highlights
Numerous fungal species, from yeasts and yeast-like fungi to molds, constitute human mycobiome and inhabit the gastrointestinal tract of healthy individuals [1]
We provide an overview of the epidemiology and molecular mechanisms of tolerance and resistance to antifungals of three most prevalent non-albicans Candida (NAC) species, namely Candida glabrata, C. parapsilosis, and C. tropicalis, the multidrug-resistant (MDR) C. auris; and most prevalent molds, namely Aspergillus fumigatus and Aspergillus terreus
Azole resistance in C. albicans has been linked with a specific segmental aneuploidy leading to the duplication of ERG11 and TAC1 genes involved in ergosterol synthesis and drug efflux, respectively [59]
Summary
From yeasts and yeast-like fungi to molds, constitute human mycobiome and inhabit the gastrointestinal tract of healthy individuals [1]. Limited in number and chemical classes, antifungal treatments and/or prophylaxis are central to reducing comorbidities and mortalities caused by fungal infections. It is considered as a driving force that replaces sensitive fungal species with other species exhibiting intrinsic and/or acquired resistance [5]. These emerging species are associated with longer hospitalizations, increased therapeutic failure, and increased costs, when compared to C. albicans, the most predominant fungal species causing bloodstream infection in humans [6,7]. Biofilms exert intrinsic resistance against antifungals, but this topic has been extensively reviewed elsewhere [13,14,15,16,17] and will not be significantly addressed in the current paper
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