Copper acts synergistically with fluconazole in Candida glabrata by compromising drug efflux, zinc homeostasis and sterol metabolism

In this study we used a transcriptomic approach to study the molecular determinants of the synergy between copper and fluconazole, in Candida glabrata, the second most frequent cause of invasive candidiasis. We demonstrate that copper acts together with fluconazole by downregulating three distinct pathways: azole efflux, ergosterol biosynthesis and zinc homeostasis. Coincidently, all these pathways are important for C. glabrata to cope with fluconazole stress. Therefore, when copper and fluconazole are combined cells fail to detoxify this drug and accumulate toxic methylated intermediates of sterol metabolism. This accumulation, possibly together with copper-induced lipid damages, should affect the activity of plasma membrane transporters, which impedes zinc uptake, leading to zinc depletion Overall design: RNA-Seq of Candida glabrata ATCC2001 strain exposed to Fluconazole, CuSO4 or both compounds when compared to untreated cells was perfomed on a Illumina NextSeq500 platform