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Review
. 2023;1(1):5.
doi: 10.1038/s44259-023-00007-2. Epub 2023 Jul 17.

Molecular mechanisms governing antifungal drug resistance

Yunjin Lee  1 , Nicole Robbins  1 , Leah E Cowen  1
Affiliations
Review

Molecular mechanisms governing antifungal drug resistance

Yunjin Lee et al. NPJ Antimicrob Resist. 2023.

Abstract

Fungal pathogens are a severe public health problem. The leading causative agents of systemic fungal infections include species from the Candida, Cryptococcus, and Aspergillus genera. As opportunistic pathogens, these fungi are generally harmless in healthy hosts; however, they can cause significant morbidity and mortality in immunocompromised patients. Despite the profound impact of pathogenic fungi on global human health, the current antifungal armamentarium is limited to only three major classes of drugs, all of which face complications, including host toxicity, unfavourable pharmacokinetics, or limited spectrum of activity. Further exacerbating this issue is the growing prevalence of antifungal-resistant infections and the emergence of multidrug-resistant pathogens. In this review, we discuss the diverse strategies employed by leading fungal pathogens to evolve antifungal resistance, including drug target alterations, enhanced drug efflux, and induction of cellular stress response pathways. Such mechanisms of resistance occur through diverse genetic alterations, including point mutations, aneuploidy formation, and epigenetic changes given the significant plasticity observed in many fungal genomes. Additionally, we highlight recent literature surrounding the mechanisms governing resistance in emerging multidrug-resistant pathogens including Candida auris and Candida glabrata. Advancing our knowledge of the molecular mechanisms by which fungi adapt to the challenge of antifungal exposure is imperative for designing therapeutic strategies to tackle the emerging threat of antifungal resistance.

Keywords: Antimicrobial resistance; Fungal evolution; Pathogens.

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Conflict of interest statement

Competing interestsL.E.C. is a co-founder and shareholder in Bright Angel Therapeutics, a platform company for development of novel antifungal therapeutics. L.E.C. is a Science Advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Antifungal mode-of-action and mechanisms of resistance.
a The echinocandins function by inhibiting (1,3)-β-D-glucan synthase, disrupting cell wall integrity and causing severe cell wall stress. Echinocandin resistance is primarily mediated by mutations in the drug target gene, FKS1, in Candida, Cryptococcus, and Aspergillus. For C. glabrata, mutations occur in both FKS1 and its paralogue FKS2. Cellular factors enabling responses to echinocandin-induced stress include the molecular chaperone Hsp90, various Hsp90 client proteins, and genes that regulate cell wall salvage signalling (e.g., compensatory upregulation of chitin synthesis). b The azoles act on the fungal cell membrane via the inhibition of lanosterol 14-α-demethylase (Erg11), which blocks ergosterol biosynthesis and results in the accumulation of a toxic sterol intermediate (14-α-methyl-3,6-diol) produced by Erg3. Azole resistance can arise through mutations in the drug target (ERG11) or target overexpression. Loss-of-function mutations in ERG3 can also confer azole resistance by blocking toxic sterol accumulation and this mechanism is contingent on Hsp90 and its client proteins. Efflux is also a major azole resistance determinant and involves the upregulation of ABC and MF transporters. Aneuploidies such as a duplication of the left arm of chromosome 5 (termed isochromosome (i5(L))) can increase dosage of the azole target Erg11 and efflux pumps. c The polyene drug amphotericin B forms extramembranous aggregates that extract ergosterol from fungal cell membranes, acting as a sterol “sponge”. While resistance remains extremely rare, it can be acquired through mutations in ergosterol biosynthesis genes resulting in the depletion of ergosterol and the accumulation of alternate sterols. As with resistance to other antifungals, resistance to amphotericin B is also contingent on Hsp90-dependent stress responses.
Fig. 2
Fig. 2. Cellular signalling governing responses to antifungal-induced stress.
A global regulator of stress response circuitry is the molecular chaperone Hsp90. Hsp90 stabilizes key cell wall and membrane integrity regulators including the protein phosphatase calcineurin, PKC-MAPK pathway members, as well as other clients that remain to be identified. Hsp90 is subject to negative regulation by casein kinase 2 (CK2) and positive regulation by lysine deacetylases (KDACs). In addition to KDACs, lysine acetyltransferases such as Gcn5 have been implicated in antifungal-induced stress. Additional modulators of cell wall integrity include the casein kinase 1 (CK1) family members, Yck2 and Hrr25, with the latter kinase also serving as a regulator of cell membrane homoeostasis. Downstream of both Hrr25 and the PKC-MAPK cascade is the SBF transcription factor (Swi4/Swi6), which is an important mediator of both cell wall and membrane integrity. There are also several additional elusive factors that remain to be identified.
Fig. 3
Fig. 3. Combinatorial strategies to combat invasive fungal infections.
Compared with monotherapy, treatment with drug combinations can improve drug efficacy and overcome resistance. a Targeting resistance mechanisms to improve antifungal efficacy due to increased bioavailability against multidrug-resistant pathogens. For example, pharmacological inhibition of efflux pump Cdr1 with a bis-benzodioxolylindolinone (azoffluxin) increases intracellular fluconazole levels, improving fluconazole activity against the emerging pathogen C. auris. b Targeting stress response regulators to enhance antifungal efficacy and impede the emergence of drug resistance. For example, pharmacological inhibition of Hsp90 with geldanamycin abrogates stress responses required to survive antifungal-induced stress.
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