Unveiling the mechanisms of in vitro evolution towards fluconazole resistance of a Candida glabrata clinical isolate: a transcriptomics approach [Mechanisms of Resistance]

Candida glabrata is an emerging fungal pathogen. Its increased prevalence is associated to its ability to rapidly develop antifungal drug resistance, particularly to azoles.

In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of a C. glabrata clinical isolate (044) from azole susceptibility to posaconazole resistance (21^st day), clotrimazole resistance (31^st day) and fluconazole and voriconazole resistance (45^th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs, when compared to the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a GOF mutation in the CgPDR1 gene, leading to the up-regulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posacozole/clotrimazole-resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posacozole/clotrimazole-resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs.

Altogether, this work provides a glimps of the transcriptomics evolution of a C. glabrata population towards multi-azole resistance, highlighting the multifactorial nature of acquisition of azole resistance, and pointing out a new player in azole resistance.

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