Introduction: Patients with invasive candidiasis in hospital settings are at severe risk of death (>30% mortality). Candida glabrata is the second most common cause of invasive candidiasis (>20%) and often C. glabrata is not susceptible to front-line antifungal medications. Over 10,000 C. glabrata invasive candidiasis infections occur yearly in the USA. Understanding metabolic processes that are unique to C. glabrata provides an appealing target for antifungal treatments. Thiamine (vitamin B1) is required by all organisms and is synthesized by most microorganisms, but not by humans. C. glabrata is partially defective in making thiamine, which means that preventing C. glabrata from acquiring thiamine is a potential therapeutic. In healthy human blood, >90% of thiamine is in the phosphorylated form, thiamine pyrophosphate (TPP), and TPP must be dephosphorylated prior to transport into C. glabrata fungal cells. We have identified CgPmu3, a thiamine-repressible thiamine phosphatase, that is required for TPP dephosphorylation and C. glabrata is unable to grow with TPP as a sole thiamine source when CgPMU3 is deleted. Treatments that decrease the amount/activity of Pmu3 or the ability to transport thiamine into the cell are viable antifungal treatments against C. glabrata.
Our work studies how thiamine metabolism is regulated in C. glabrata at the level of thiamine biosynthetic promoters and transcriptional activators. By understanding how these promoters are regulated, rational strategies to alter the expression of thiamine starvation genes can be explored. Our work also examines whether thiamine nutrient status and the presence of CgPmu3 (and other thiamine regulated genes) influences the ability of C. glabrata to persist and multiply in phagocytic, macrophage-like cells. As clearance of C. glabrata is mediated by phagocytic cells. If the ability to acquire thiamine is defective in C. glabrata, then this fungal pathogen should be more easily cleared from the bloodstream by phagocytic cells. Long-term our work will provide a better understanding of the thiamine biosynthetic and acquisition pathway and determine if this pathway is a suitable target for the development of anti-fungal compounds.