The mechanisms behind rising antifungal drug resistance Nature antifungal resistance antifungalresistance mechanisms resistance drugresistance
By Neha MathurJul 19 2023Reviewed by Sophia Coveney In a recent study published in npj Antimicrobials and Resistance, researchers addressed the issue of the rise of antifungal drugs-resistant infections and the advent of multidrug-resistant fungal pathogens. In addition, they described the strategies used by fungal pathogens to evolve resistance and the mechanism governing the same.
Only three classes of drugs - polyenes, azoles, and echinocandins - are currently available to combat these lethal fungal pathogens. Amphotericin B, a polyene drug, is the treatment of choice for infections caused by C. neoformans. It exhibits broad-spectrum activity against many yeast and mold species but induces host toxicity too, which disfavors its wide clinical use.
Modes of acquiring antifungal drug resistance Drug target alteration Published literature describes over 140 unique sterol 14-demethylase amino acid substitutions in C. albicans, a structural analysis of which found that while some substitutions directly affected azole binding, those occurring on the proximal surface indirectly contributed to azole resistance. Some ERG11 mutations also occurred in azole-resistant clinical isolates of C. neoformans.
Related StoriesNote that resistance to echinocandin frequently involves mutations in genes encoding the drug target, FKS1 and FKS2. These genes help in the synthesis of β-1,3-glucan, a core component of the fungal cell wall during vegetative growth and sporulation, respectively. Genomic plasticity Fungal pathogens have remarkable genomic plasticity; accordingly, they alter their genomes rapidly via aneuploidy, loss of heterozygosity events, and copy number variations , which amplify large genomic regions. In addition, heteroresistance gave rise to highly azole-resistant fungal populations. A recent study also demonstrated horizontal gene transfer -mediated antifungal resistance in A. fumigatus.
Against echinocandins, C. albicans and A. fumigatus upregulate chitin, an essential fungal cell wall polysaccharide, which helps compensate for cellular stress induced by the inhibition of glucan synthase. Drug-induced or genetic inhibition of lysine deacetylases hampers the physical interaction between Hsp90 and calcineurin proteins needed to mount cellular stress responses, often resulting in azole resistance. In addition, lysine acetyltransferases, such as Gcn5, mediate resistance in Candida species.
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