What ‘Omics can tell us about antifungal adaptation

Abstract

Invasive candidiasis, the most frequent healthcare associated invasive fungal infection, is commonly caused by Candida albicans. However, in recent years other antifungal-resistant Candida species – namely C. glabrata and C. auris – have emerged as a serious matter of concern. Much of our understanding of the mechanisms regulating antifungal resistance and tolerance relies on studies utilising C. albicans, C. glabrata, and the model yeast Saccharomyces cerevisiae. ‘Omics studies have been used to describe alterations in metabolic, genomic and transcriptomic expression profiles upon antifungal treatment of fungal cells. The physiological changes identified by these approaches could significantly affect fungal fitness in the host and survival during antifungal challenge, as well as provide further understanding of clinical resistance. Thus, this review aims to comparatively address ‘omics data for C. albicans, C. glabrata, and S. cerevisiae published from 2000 to 2021 to identify what these technologies can tell us regarding cellular responses to antifungal therapy. We will also highlight possible effects on pathogen survival and identify future avenues for antifungal research.

Mod5 mediates a molecular trade-off between optimal gene expression and antifungal resistance.

“…2B ; Table S6,7 ). Similar changes of the transmembrane transporter regulation as well as DNA repair/recombination activity were also reported in other fungal species like S. cerevisiae upon 5-FC treatment (70,73,74).…”

“…A closer interrogation of the transcriptional reprogramming induced upon 5-FC treatment of the wild type and knockout indicated similar pronounced adaptive stress responses. This included the prevention of DNA damage and translational impedance caused by 5-FC/5-FU, alongside a deregulation of various transmembrane transporters consistent with observations from other non-pathogenic and pathogenic fungi ( Fig.2B, Table S2,6-8 ; (66,70–72)). Transcriptomics revealed an induction of amino acid starvation responsive genes in Δ mod5 , which was also partly observed in non-stressed conditions ( Fig.…”

“…2B ; Table S6,7 ), including many ribosome biogenesis and rRNA processing genes. Similar effects upon 5-FC treatment could be observed in other pathogenic fungi like C. albicans and C. glabrata , probably indicating a compensatory effect to cope with increased translational defects (70–72). Both strains appeared to activate DNA damage response pathways (e.g.…”

“…fluorouridine monophosphate (5-FUMP); however, deletion of urkA only confers slight resistance(69), suggesting that deregulation of the salvage pathway factors are not likely responsible for the ∆mod5 phenotype.A closer interrogation of the transcriptional reprogramming induced upon 5-FC treatment of the wild type and knockout indicated similar pronounced adaptive stress responses. This included the prevention of DNA damage and translational impedance caused by 5-FC/5-FU, alongside a deregulation of various transmembrane transporters consistent with observations from other non-pathogenic and pathogenic fungi (Fig.2B, TableS2,6-8;(66,(70)(71)(72)). …”

Adaptation to complex environments reveals pervasive trade-offs and genomic targets with large pleiotropic effects

“…We saw that populations exposed to fluconazole had an enrichment of mutations at both the base pair and gene level. Fluconazole has known genotoxic effects, increasing the rate of DNA damage (Silva et al 2019; Yüzbaşioğlu et al 2008; Ribeiro et al 2022). Increased parallelism at the genomic level may be due to increased mutational availability in antifungal-exposed populations.…”