Dysregulation of ClpP by Small-Molecule Activators Used Against Xanthomonas oryzae pv. oryzae Infections

Rice bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae ( Xoo ) is considered a destructive plant bacterial disease. The looming crisis of antibiotic resistance necessitates the discovery of antibiotics with new modes of action. Activated caseinolytic protease P (ClpP) can degrade bacterial FtsZ proteins that are essential for cell division; thus, we hypothesized that small-molecule-induced dysregulation of Xoo ClpP may result in degradation of Xoo FtsZ to treat leaf blight diseases. In this work, we have determined the crystal structures of Xoo ClpP, and its mutant bound with ADEP4, which revealed the action modes of Xoo ClpP assemblies and Xoo FtsZ degradation by dysregulated Xoo ClpP in the presence of small-molecule activators, such as ONC212 and ADEP4. Additionally, an antibacterial assessment demonstrated that ONC212 displays excellent activity against Xoo and prevents rice bacterial leaf blight in vivo . Thus, these unique antibacterial effects of small-molecule activators of Xoo ClpP represent a potential strategy for the development of agricultural antibiotics by targeting bacterial ClpP.