Unraveling the sugar metabolism of Candida albicans to find new antifungal drugs

Candida albicans is an opportunistic fungal pathogen which infection rate became more frequent over the last years. Another problem is their rising resistance against the available antifungal drugs on the market, like fluconazole. Therefore, C. albicans is a relevant health problem and there is an urgent need for new antifungal drugs with a complete novel mode of action to counteract the spread of this fungus. To colonize the human body this pathogen has different virulence factors, for example morphogenesis, adhesion and biofilm formation. Some of these virulence factors are under control of the PKA pathway. This pathway can be activated by different external stimuli, for example glucose. The exact mechanism of how glucose has an effect on PKA is yet not known, but Cdc25 and Ras play an important role in this mechanism. Now, over the last years it became more and more clear that the central metabolism plays an important role in the regulation of the virulence factors of this pathogen. For example, when the activators of glycolytic enzymes are abolished, there also is an abolished virulence in these cells. So therefore, we want to see what the link is between glucose metabolism and PKA activation and thereby the activation of the virulence factors. Because if we know this link, we have new targets and we can search for antifungal drugs with a complete novel mode of action. Therefore, we will focus on the first step of glycolysis, the conversion of glucose into glucose-6-phosphate. In Saccharomyces cerevisiae, this step is mainly catalyzed by Hxk2, so therefore we made an alignment and we found four enzymes in C. albicans with a homologues structure compared to ScHxk2, CaHxk1, CaHxk2, CaGlk1 and CaGlk4. To our surprise, almost nothing was known about these kinases, so therefore we will make different deletion strains of these kinases to see what the effect is of these deletions on the virulence of this pathogen. If we know this, we will go further in the pathway and we will investigate how glucose is able to activate Cdc25 and Ras. From literature, we know that in S. cerevisiae Fructose-1,6-bisphosphate is able to bind with Cdc25 and thereby causes the activation of the Ras/cAMP/PKA pathway. So now, we want to see if this also happens in C. albicans. At last, we will search for inhibitors of the kinases with the highest effect on virulence.