Characterization of the mechanism of action of the fungicide fenpicoxamid and its metabolite UK‐2A

• Published in: Pest management science 2018-02, Vol.74 (2), p.489-498
• Main Authors: Young, David H, Wang, Nick X, Meyer, Stacy T, Avila‐Adame, Cruz
• Format: Article
• Language: English
• Subjects: Acids; Active control; Amino Acid Substitution; Amino acids; Antimycin A; Ascomycota - drug effects; benzimidazole fungicides; Benzimidazoles; binding site; Binding sites; Botrytis - drug effects; Botrytis cinerea; Cross-resistance; Cytochrome; Cytochrome b; Cytochrome c; Docking; fenpicoxamid; Fungi; Fungicides; Fungicides, Industrial - pharmacology; Inatreq™ active; Lactones - pharmacology; mechanism of action; Membrane potential; Metabolism; metabolites; Mitochondria; mitochondrial membrane; Mode of action; modeling; Mycosphaerella graminicola; NADH dehydrogenase; Pest control; Pesticides; Plant Diseases - prevention & control; Pyridines - pharmacology; Quinones; Reductase; resistance; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Spores; Strobilurin; UK‐2A; Zymoseptoria tritici
• ISSN: 1526-498X; 1526-4998
• DOI: 10.1002/ps.4743

BACKGROUND Fenpicoxamid is a new fungicide for control of Zymoseptoria tritici, and is a derivative of the natural product UK‐2A. Its mode of action and target site interactions have been investigated. RESULTS UK‐2A strongly inhibited cytochrome c reductase, whereas fenpicoxamid was much less active, consistent with UK‐2A being the fungicidally active species generated from fenpicoxamid by metabolism. Both compounds caused rapid loss of mitochondrial membrane potential in Z. tritici spores. In Saccharomyces cerevisiae, amino acid substitutions N31K, G37C and L198F at the Qi quinone binding site of cytochrome b reduced sensitivity to fenpicoxamid, UK‐2A and antimycin A. Activity of fenpicoxamid was not reduced by the G143A exchange responsible for strobilurin resistance. A docking pose for UK‐2A at the Qi site overlaid that of antimycin A. Activity towards Botrytis cinerea was potentiated by salicylhydroxamic acid, showing an ability of alternative respiration to mitigate activity. Fungitoxicity assays against Z. tritici field isolates showed no cross‐resistance to strobilurin, azole or benzimidazole fungicides. CONCLUSION Fenpicoxamid is a Qi inhibitor fungicide that provides a new mode of action for Z. tritici control. Mutational and modeling studies suggest that the active species UK‐2A binds at the Qi site in a similar, but not identical, fashion to antimycin A. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. Fenpicoxamid is a new fungicide for control of Zymoseptoria tritici and is a derivative of the natural product UK‐2A. Its fungicidal mechanism of action and target site interactions are explored.