Natural-product repurposing for novel reactive oxygen species inducer discovery: bactericidal profiling and structure-activity relationship of ellipticine and its analogs

The development of therapeutic agents targeting oxidative stress induction to disrupt bacterial redox defenses has become a prominent strategy in antimicrobial research. To augment the structural diversity of reactive oxygen species (ROS) inducers for bacterial infection control, it was implemented a natural product repurposing strategy, through which ellipticine—a plant-derived alkaloid—was identified as an innovative agent effective against Xanthomonas oryzae pv. oryzae infecting rice. Notably, ellipticine demonstrated significantly superior antibacterial activity against Xanthomonas oryzae pv. oryzae (EC₅₀ = 0.71 ± 0.12 μg/mL) compared to the control thiodiazole copper (TC, EC₅₀ = 80.38 ± 1.36 μg/mL), with enhancement of 113-fold. Mechanistic investigations revealed that ellipticine induced an explosive burst of ROS within bacterial cells, triggering the bacterial apoptotic cascade and compromising cell membrane integrity. Interestingly, validation using a rice model further demonstrated that ellipticine exhibited protective and curative effects against bacterial leaf blight at rates of 52.75 % and 47.26 %, respectively, nearly double those of TC (protection rate: 28.55 %; curative rate: 26.47 %). Additionally, ellipticine exhibited favorable drug-like properties. This is the first report proposing ellipticine as a botanical bactericide candidate via ROS-mediated bactericidal mechanism, providing a significant example for the development of new bactericides. This research not only bridges a critical gap in understanding ROS-mediated antibacterial mechanisms in natural product development but also lays a theoretical foundation for the optimal design of antibacterial molecules targeting the ROS pathway.