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Fungal infections, especially candidiasis and aspergillosis, claim a high fatality rate. Fungal cell growth and function requires ATP, which is synthesized mainly through oxidative phosphorylation, with the key enzyme being F 1 F o -ATP synthase. Here, we show that deletion of the  Candida albicans  gene encoding the δ subunit of the F 1 F o -ATP synthase ( ATP16 ) abrogates lethal infection in a mouse model of systemic candidiasis. The deletion does not substantially affect in vitro fungal growth or intracellular ATP concentrations, because the decrease in oxidative phosphorylation-derived ATP synthesis is compensated by enhanced glycolysis. However, the  ATP16 -deleted mutant displays decreased phosphofructokinase activity, leading to low fructose 1,6-bisphosphate levels, reduced activity of Ras1-dependent and -independent cAMP-PKA pathways, downregulation of virulence factors, and reduced pathogenicity. A structure-based virtual screening of small molecules leads to identification of a compound potentially targeting the δ subunit of fungal F 1 F o -ATP synthases. The compound induces in vitro phenotypes similar to those observed in the  ATP16 -deleted mutant, and protects mice from succumbing to invasive candidiasis. Our findings indicate that F 1 F o -ATP synthase δ subunit is required for  C. albicans  lethal infection and represents a potential therapeutic target.

The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans