The discovery of natural 4'-demethylepipodophyllotoxin from renewable Dysosma versipellis species as a novel bacterial cell division inhibitor for controlling intractable diseases in rice

Natural products (NPs) are inexhaustible wellsprings for new agrochemicals discovery. To excavate novel natural products-based antibacterial leads or candidates potentially targeting FtsZ (filamentous temperature-sensitive protein Z) which is widely regarded as a promising antibacterial target for novel drug discovery, herein, a rapid and efficient screening platform was initially established to disclose the potential FtsZ inhibitors from a variety of commercial natural products. Screening results revealed that 4'-demethylepipodophyllotoxin (DMEP) from renewable Dysosma versipellis (D. versipellis) species could distinctly decrease the XooFtsZ' GTPase activity and afforded a ponderable bacteriostatic effect (EC50 = 38.7 mg L-1) against Xanthomonas oryzae pv. oryzae (Xoo). Further explorations found that DMEP could disorganize the assembly dynamics of XooFtsZ, and thereby yielding long and filamentous Xoo cells from the transmission electron microscopic and fluorescence microscopic imaging. Molecular docking study showed that DMEP displayed strong interactions with Asp38 and Arg205 residues of XooFtsZ, indicating that a natural potential FtsZ inhibitor was discovered gradually. The following bioassay result against rice bacterial blight in vivo presented good curative activity (50.0% at 200 mg L-1) and protective activity (46.8% at 200 mg L-1). Given that natural DMEP has many sites for structural modification, therefore, it can concurrently serve as a novel lead compound for exploring highly bioactive FtsZ inhibitors based on the molecular skeleton of DMEP.