The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

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-albicansCandida 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.

Keywords: Aspergillus fumigatus; Aspergillus terreus; Candida auris; Candida glabrata; Candida parapsilosis; Candida tropicalis; antifungal resistance mechanisms.

Figure 1

Phylogenetic tree of Candida species studied in the current review, i.e., C. glabrata, C. parapsilosis, C. tropicalis, and C. auris (highlighted in blue). This tree was constructed using maximum likelihood of 11,570 core genes based on 1000 replicates. Asterikes does not serve any specific defnitions. This figure was adopted permission from Munoz et al., 2018 [20].

Figure 2

Mechanisms of antifungal tolerance. The mechanisms include rapid coordination of numerous signal transduction pathways that depend on the antifungal drug used. Echinocandin tolerance mechanism, known as the cell wall integrity pathway, involves protein kinase C (PKC), high-osmolarity glycerol (HOG), and calcineurin pathways, followed by the overexpression of chitin synthase, and FKS1 and FKS2 to compensate for the reduction of β-1,3-d-glucan level in the cell wall. Membrane integrity pathway orchestrates the azole tolerance pathways, which includes PKC and calcineurin pathways. As it is shown, HSP90 plays a critical role in antifungal tolerance by stabilizing the key regulatory proteins.

Figure 3

Pdr1p contains four domains. Numerous GOF mutations (black bars) can cause azole resistance. Adopted the permission from Ferrari et al., 2009 [98].

Figure 4

Fluconazole resistance is mediated by both Upc2p and Pdr1p in C. glabrata.

Figure 5

Whole-genome sequence analysis of the US C. auris (up to 2018) isolates reveals the existence of four major clades. Isolates representing all identified clades have been recovered from the U.S. The Iranian clade is not shown in this figure. Adopted the permission from Chow et al., 2018 [201].