Dysregulation of ClpP by Small-Molecule Activators Used Against Xanthomonas oryzae pv. oryzae Infections,Journal of Agricultural and Food Chemistry

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Dysregulation of ClpP by Small-Molecule Activators Used Against Xanthomonas oryzae pv. oryzae Infections
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2021-07-03 , DOI: 10.1021/acs.jafc.1c01470
Teng Yang _{1,

2} , Tao Zhang ₂ , Xiang Zhou ₁ , Pengyu Wang _{2,

3} , Jianhua Gan ₄ , Baoan Song ₁ , Song Yang ₁ , Cai-Guang Yang _{2,

3,

5}

Affiliation

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 XooClpP may result in degradation of XooFtsZ to treat leaf blight diseases. In this work, we have determined the crystal structures of XooClpP, and its mutant bound with ADEP4, which revealed the action modes of XooClpP assemblies and XooFtsZ degradation by dysregulated XooClpP 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 XooClpP represent a potential strategy for the development of agricultural antibiotics by targeting bacterial ClpP.

中文翻译：

用于对抗米黄单胞菌 pv的小分子活化剂对 ClpP 的失调。米线虫感染

米黄单胞菌引起的水稻白叶枯病。稻瘟病( Xoo ) 被认为是一种破坏性的植物细菌病害。迫在眉睫的抗生素耐药性危机需要发现具有新作用模式的抗生素。活化的酪蛋白水解蛋白酶 P (ClpP) 可以降解细胞分裂所必需的细菌 FtsZ 蛋白；因此，我们假设小分子诱导的Xoo ClpP失调可能导致Xoo FtsZ降解以治疗叶枯病。在这项工作中，我们确定了Xoo ClpP的晶体结构及其与 ADEP4 结合的突变体，揭示了Xoo ClpP 组件和Xoo的作用模式在小分子激活剂（如 ONC212 和 ADEP4）存在下，失调的Xoo ClpP 对FtsZ 的降解。此外，抗菌评估表明 ONC212 对Xoo显示出优异的活性，并在体内防止水稻细菌性叶枯病。因此，Xoo ClpP小分子激活剂的这些独特抗菌作用代表了通过靶向细菌 ClpP 开发农业抗生素的潜在策略。

更新日期：2021-07-14

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