Antifungal activity of cinnamic acid derivatives involves inhibition of benzoate 4‐hydroxylase (CYP53)

• Published in: Journal of applied microbiology 2014-04, Vol.116 (4), p.955-966
• Main Authors: Korošec, B, Sova, M, Turk, S, Kraševec, N, Novak, M, Lah, L, Stojan, J, Podobnik, B, Berne, S, Zupanec, N, Bunc, M, Gobec, S, Komel, R
• Format: Article
• Language: English
• Subjects: active sites; antifungal activity; antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; antifungal properties; Ascomycota - drug effects; Aspergillus niger; Benzoate 4-Monooxygenase - antagonists & inhibitors; Benzoate 4-Monooxygenase - chemistry; Benzoate 4-Monooxygenase - metabolism; Biological and medical sciences; Catalytic Domain; Cinnamates - chemistry; Cinnamates - metabolism; Cinnamates - pharmacology; cinnamic acid; Cochliobolus lunatus; Curvularia lunata; CYP53 inhibition; cytochrome P-450; cytochrome P450, benzoate 4‐monooxygenase; drugs; enzyme activity; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; enzymes; Eukaryotes; eukaryotic cells; Fundamental and applied biological sciences. Psychology; Fungi; Fungi - enzymology; mechanism of action; metabolism; Microbiology; pathogens; Pharmacology; Plant pathology; Pleurotus - drug effects; Pleurotus ostreatus; potential antifungal drugs
• ISSN: 1364-5072; 1365-2672
• DOI: 10.1111/jam.12417

AIMS: CYP53A15, from the sorghum pathogen Cochliobolus lunatus, is involved in detoxification of benzoate, a key intermediate in aromatic compound metabolism in fungi. Because this enzyme is unique to fungi, it is a promising drug target in fungal pathogens of other eukaryotes. METHODS AND RESULTS: In our work, we showed high antifungal activity of seven cinnamic acid derivatives against C. lunatus and two other fungi, Aspergillus niger and Pleurotus ostreatus. To elucidate the mechanism of action of cinnamic acid derivatives with the most potent antifungal properties, we studied the interactions between these compounds and the active site of C. lunatus cytochrome P450, CYP53A15. CONCLUSION: We demonstrated that cinnamic acid and at least four of the 42 tested derivatives inhibit CYP53A15 enzymatic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: By identifying selected derivatives of cinnamic acid as possible antifungal drugs, and CYP53 family enzymes as their targets, we revealed a potential inhibitor‐target system for antifungal drug development.