Dysregulation of ClpP by Small-Molecule Activators Used Against <i>Xanthomonas oryzae pv. oryzae</i> Infections

Abstract

Rice bacterial leaf blight caused by <i>Xanthomonas oryzae pv. oryzae</i> (<i>Xoo</i>) 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 <i>Xoo</i>ClpP may result in degradation of <i>Xoo</i>FtsZ to treat leaf blight diseases. In this work, we have determined the crystal structures of <i>Xoo</i>ClpP, and its mutant bound with ADEP4, which revealed the action modes of <i>Xoo</i>ClpP assemblies and <i>Xoo</i>FtsZ degradation by dysregulated <i>Xoo</i>ClpP in the presence of small-molecule activators, such as ONC212 and ADEP4. Additionally, an antibacterial assessment demonstrated that ONC212 displays excellent activity against <i>Xoo</i> and prevents rice bacterial leaf blight <i>in vivo</i>. Thus, these unique antibacterial effects of small-molecule activators of <i>Xoo</i>ClpP represent a potential strategy for the development of agricultural antibiotics by targeting bacterial ClpP.