In recent years several promising antifungal targets have been under exploration. One of such is also fungal CYP53, family of highly conserved proteins observed in a number of pathogenic fungi, such as Aspergillus fumigatus and Gibberella zeae. In our recent study we identified benzoate para-hydroxylase (CYP53A15 or BPH) as a unique enzyme involved in detoxification of benzoate, a key intermediate in metabolism of aromatic compounds in fungi. High specificity and absence of homologue in higher eukaryotes assign CYP53A15 as interesting drug target. We have also revealed inhibition of CYP53A15 with natural compounds, such as isoeugenol, thymol, trans-cinnamic acid and shown their antifungal potential. Among 25 cinnamic acid derivatives tested, 4 compounds have shown antifungal potential. Two of them were also evaluated as inhibitors of CYP53A15 activity and were selected for further optimization of new lead structures
F.02 Acquisition of new scientific knowledge
COBISS.SI-ID: 5192218CYP53A15, 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. In order 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 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.
B.04 Guest lecture
COBISS.SI-ID: 30547417