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

Shuixiu Li, Yajing Zhao, Yishan Zhang, Yanli Zhang, Zhanpeng Zhang, Chuanyan Tang, Luobei Weng, Xiaohong Chen, Gehua Zhang () and Hong Zhang ()
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Shuixiu Li: The First Affiliated Hospital of Jinan University
Yajing Zhao: The First Affiliated Hospital of Jinan University
Yishan Zhang: The First Affiliated Hospital of Jinan University
Yanli Zhang: The First Affiliated Hospital of Jinan University
Zhanpeng Zhang: The First Affiliated Hospital of Jinan University
Chuanyan Tang: The First Affiliated Hospital of Jinan University
Luobei Weng: The First Affiliated Hospital of Jinan University
Xiaohong Chen: The Third Affiliated Hospital of Sun Yat-Sen University
Gehua Zhang: The Third Affiliated Hospital of Sun Yat-Sen University
Hong Zhang: The First Affiliated Hospital of Jinan University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26313-9

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