Abstract
Anti-microbial resistance (AMR) is currently one of the most serious threats to global human health and, appropriately, research to tackle AMR garnishes significant investment and extensive attention from the scientific community. However, most of this effort focuses on antibiotics, and research into anti-fungal resistance (AFR) is vastly under-represented in comparison. Given the growing number of vulnerable, immunocompromised individuals, as well as the positive impact global warming has on fungal growth, there is an immediate urgency to tackle fungal disease, and the disturbing rise in AFR. Chromatin structure and gene expression regulation play pivotal roles in the adaptation of fungal species to anti-fungal stress, suggesting a potential therapeutic avenue to tackle AFR. In this review we discuss both the genetic and epigenetic mechanisms by which chromatin structure can dictate AFR mechanisms and will present evidence of how pathogenic yeast, specifically from the Candida genus, modify chromatin structure to promote survival in the presence of anti-fungal drugs. We also discuss the mechanisms by which anti-chromatin therapy, specifically lysine deacetylase inhibitors, influence the acquisition and phenotypic expression of AFR in Candida spp. and their potential as effective adjuvants to mitigate against AFR.
Highlights
Anti-microbial resistance (AMR) is currently one of the most serious threats to global human health and, appropriately, research to tackle AMR garnishes significant investment and extensive attention from the scientific community
A subsequent in vivo analysis showed that MGCD290 synergized with fluconazole in an invasive candidiasis (C. albicans) model, and mice treated with both drugs showed a significantly lower kidney fungal load and increased survival than those receiving fluconazole alone [170]
We have presented a framework to think about how epigenetic mechanisms might facilitate anti-fungal resistance (AFR) through an initial phase of phenotypic resistance, that provides for a small fraction of cells within a population an increased opportunity to acquire genetic resistance
Summary
Candidiasis, one of the most widespread human fungal infections, is caused by yeast species from the Candida genus. C. albicans causes most candidiasis cases, non-C. albicans Candida [NCAC] infections have progressively increased in frequency over the past two decades [2,7] Of these species, C. glabrata is the most frequently isolated NCAC species in global surveillance studies, representing 10-18% of all Candida isolates [8]. The molecular bases of intrinsic resistance in Candida spp. are unknown [19,20], recent research suggests that in C. auris at least, transcriptional regulation is key [21]. The biggest threat these fungi pose to global health is the ease with which Candida species acquire anti-fungal resistance. The contribution of fungal chromatin structure and epigenetic mechanisms to anti-fungal adaptation and resistance is an under-explored aspect of this phenomenon, in spite of growing evidence supporting its therapeutic potential [30,31]
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