Glucose metabolic reprogramming and modulation in glycerol biosynthesis regulates drug resistance in clinical isolates of Candida.

This article focuses on elucidating novel molecular mechanisms underlying antifungal drug resistance in clinical isolates of Candida species, particularly Candida albicans and Candida glabrata, from the Kashmir valley in northern India. The study found that drug-resistant C. albicans isolates exhibit increased expression of hexokinase 2 (Hxk2) and glucose-6-phosphate dehydrogenase (G6pd), leading to enhanced glucose fermentation (akin to the Warburg effect), elevated ATP and lactate production, and improved reactive oxygen species (ROS) scavenging via NADPH generation. In contrast, drug-resistant C. glabrata isolates rely on glycerol metabolism for resistance, accumulating intracellular glycerol as an osmolyte through activation of the Hog1 mitogen-activated protein kinase (Hog1-MAPK) pathway to better withstand environmental stresses. Pharmacological inhibition of Hxk2 and G6pd reversed drug resistance in C. albicans but not in C. glabrata, highlighting distinct metabolic adaptations driving antifungal resistance in these species. These findings suggest that targeting intermediary metabolism may offer alternative therapeutic strategies against drug-resistant Candida infections.