Targeting a cryptic Magnaporthe oryzae-specific pocket in succinate dehydrogenase to combat rice blast.

The global efficacy of succinate dehydrogenase inhibitors (SDHIs), a leading class of fungicides, is increasingly threatened by resistance, driven largely by their shared binding mode at the conserved ubiquinone-binding (Q) site. This challenge is particularly acute for rice blast, as no SDHI is registered for this disease and available compounds offer limited protection while remaining vulnerable to Q-site mutations. In this study, we identified a previously unrecognized, pathogen-adaptive pocket within the SDH complex of Magnaporthe oryzae, which is structurally distinct from the canonical Q site. Leveraging this finding, we performed virtual screening and identified PD13, a phenylhydrazine-derived inhibitor predicted to bind this region. Notably, PD13 impaired UQ recognition and catalysis, suppressed SDH activity, and triggered ATP depletion, while demonstrating field efficacy comparable to the conventional fungicide tricyclazole. Importantly, it remained fully active against a strain cross-resistant to multiple commercial SDHIs and exhibited low toxicity toward non-target organisms. Beyond introducing a new compound, this study expands the druggable landscape of a well-characterized target and provides a strategic proof of concept for exploiting noncanonical pockets in established fungicide targets.