Fungicidal Action of the Triphenylphosphonium-Driven Succinate Dehydrogenase Inhibitors Is Mediated by Reactive Oxygen Species and Suggests an Effective Resistance Management Strategy

Succinate dehydrogenase (SDH) is an effective target of SDH inhibitor (SDHI) fungicides which received more and more attention in recent years. However, there is no good solution to their rapidly growing drug resistance caused by frequent use. In this study, three triphenylphosphonium (TPP)-conjugated boscalid analogues were synthesized and tested for antifungal activities. They all, especially 2c, exhibited enhanced fungicidal activity and broader spectra compared to boscalid. The action mechanism study revealed that 2c was also an SDH inhibitor acting on the Qp site. However, the rapid accumulation of 2c in mitochondria because of TPP-targeting triggered reactive oxygen species burst in mitochondria, resulting in irreversible damage to the mitochondrial structure and function. Thus, 2c made the fungicidal activity output mode changing from mainly relying on ATP production inhibition (as traditional SDHIs) to significant damage of the cell structure and functions. This mechanism change made it difficult for plant pathogenic fungi to develop resistance to 2c and its analogues, which was of great significance for the increasingly challenging management of field resistance to SDHI fungicides.