Phenazine‐1‐Carboxamide from <i>Streptomyces</i> Suppresses <i>Phytophthora nicotianae</i> via CDC48‐Targeted Mitochondrial Disruption

Phytophthora nicotianae is a plant-pathogenic oomycete, posing a serious threat to global agriculture due to its highly destructive infections and challenges in management. To explore a biologically based disease management strategy, we investigated Streptomyces ardesiacus HL-06, which produces phenazine-1-carboxamide (PCN), a potent anti-oomycete metabolite that effectively suppresses the growth of P. nicotianae in vitro and reduces tobacco black shank severity by over 80% under field conditions, surpassing the efficacy of commercial fungicides. Mechanistically, we identified CDC48, a AAA+ ATPase essential for mitochondrial homeostasis, as the direct molecular target of PCN. Drug affinity responsive target stability (DARTS), molecular docking, and isothermal titration calorimetry revealed that PCN binds to CDC48's ATPase domain, thereby disrupting mitochondrial protein quality control. This interaction leads to mitochondrial cristae loss, ATP synthase inhibition, and reactive oxygen species (ROS) accumulation, ultimately triggering oomycete apoptosis. This is the first report of a phenazine compound targeting a eukaryotic AAA+ ATPase, revealing a novel mode of action against oomycete pathogens. Our findings integrate microbial ecology with chemical biology, positioning PCN as a promising eco-friendly candidate for sustainable plant disease management.