Epigenetic Regulation of Antifungal Drug Resistance

Abstract

In medical mycology, epigenetic mechanisms are emerging as key regulators of multiple aspects of fungal biology ranging from development, phenotypic and morphological plasticity to antifungal drug resistance. Emerging resistance to the limited therapeutic options for the treatment of invasive fungal infections is a growing concern. Human fungal pathogens develop drug resistance via multiple mechanisms, with recent studies highlighting the role of epigenetic changes involving the acetylation and methylation of histones, remodeling of chromatin and heterochromatin-based gene silencing, in the acquisition of antifungal resistance. A comprehensive understanding of how pathogens acquire drug resistance will aid the development of new antifungal therapies as well as increase the efficacy of current antifungals by blocking common drug-resistance mechanisms. In this article, we describe the epigenetic mechanisms that affect resistance towards widely used systemic antifungal drugs: azoles, echinocandins and polyenes. Additionally, we review the literature on the possible links between DNA mismatch repair, gene silencing and drug-resistance mechanisms.

Anaerobic growth and drug susceptibility of versatile fungal pathogen Scedosporium apiospermum

“… 9 , 17 Conditional morphological and physiological changes in pathogens induced by hypoxic or anoxic conditions of infection sites may alter drug susceptibility and tolerance patterns. 9 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Compared to genetic mutations, the rate of development of phenotypic heterogeneity due to changes in growth conditions and environment is 10–90% higher in fungi. 17 In this study, we show that fungal growth under anaerobic conditions alters pigmentation and sporulation of the tested organisms.…”

Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance

“…65 However, mutations in ergosterol biosynthesis enzymes, including ERG2, ERG3, ERG5, and ERG11, can contribute to the reduction of AmB potency against C. albicans . 66 Mutations in ERG2, ERG6, and ERG11 were found in polyene-resistant C. glabrata clinical isolates, 67 and in ERG1, ERG2, ERG6, and ERG13 in the case of C. auris . 68 A recent investigation on C. auris emphasized the potential role of drug transporters in amphotericin B resistance, where whole-genome sequencing of polyene-resistant clinical isolates showed four non-synonymous mutations, one of which was in a potential membrane transporter.…”