RT Journal Article
SR Electronic
T1 The landscape of toxic intermediates in the metabolic networks of pathogenic fungi reveals targets for antifungal drugs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.05.459012
DO 10.1101/2021.09.05.459012
A1 Jan Ewald
A1 Paul Mathias Jansen
A1 Sascha Brunke
A1 Davina Hiller
A1 Christian H. Luther
A1 Humbert González-Díaz
A1 Marcus T. Dittrich
A1 André Fleißner
A1 Bernhard Hube
A1 Stefan Schuster
A1 Christoph Kaleta
YR 2021
UL http://biorxiv.org/content/early/2021/09/06/2021.09.05.459012.abstract
AB The burden of fungal infections for humans, animals and plants is widely underestimated and comprises deadly infections as well as great economic costs. Despite that, antifungal drugs are scarce and emergence of resistance in fungal strains contributes to a high mortality. To overcome this shortage, we propose toxic intermediates and their controlling enzymes in metabolic pathways as a resource for new targets and provide a web-service, FunTox-Networks to explore the landscape of toxic intermediates in the metabolic networks of fungal pathogens. The toxicity of metabolites is predicted by a new random forest regression model and is available for over one hundred fungal species. Further, for major fungal pathogens, metabolic networks from the KEGG database were enriched with data of toxicity and regulatory effort for each enzyme to support identification of targets. We determined several toxic intermediates in fungal-specific pathways like amino acid synthesis, nitrogen and sulfur assimilation, and the glyoxylate bypass. For the latter, we show experimentally that growth of the pathogen Candida albicans is inhibited when the detoxifying enzymes Mls1 and Hbr2 are deleted and toxic glyoxylate accumulates in the cell. Thus, toxic pathway intermediates and their controlling enzymes represent an untapped resource of antifungal targets.Competing Interest StatementThe authors have declared no competing interest.