Abstract
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 F1Fo-ATP synthase. Here, we show that deletion of the Candida albicans gene encoding the δ subunit of the F1Fo-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 F1Fo-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 F1Fo-ATP synthase δ subunit is required for C. albicans lethal infection and represents a potential therapeutic target.
Highlights
Fungal infections, especially candidiasis and aspergillosis, claim a high fatality rate
These results indicate that δ subunit deletion abrogates C. albicans-mediated lethal infection
We showed that the F1Fo-ATP synthase δ subunit is required for lethal infection in Candida albicans
Summary
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 F1Fo-ATP synthase. We show that deletion of the Candida albicans gene encoding the δ subunit of the F1Fo-ATP synthase (ATP16) abrogates lethal infection in a mouse model of systemic candidiasis. The ATP that is necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation (OXPHOS), with the key enzyme being F1Fo-ATP synthase[4]. It remains unclear how this enzyme affects pathogenicity. Deleting the δ subunit gene does not affect intracellular ATP levels, but reduces phosphofructokinase (Pfk1) activity, decreases fructose 1,6-bisphosphate (FBP) levels, blocks Ras1-dependent and -independent cAMP-PKA pathways, and downregulates virulence factors. A small molecule potentially targeting the δ subunit suppresses virulence factor expression in vitro and protects mice from morbidity and mortality upon systemic C. albicans infection
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