The widespread and repeated use of broad-spectrum bactericides has led to an increase in resistance. Developing novel broad-spectrum bactericides cannot solve the resistance problem, and may even aggravate it. The design of specific and selective bactericides has become urgent. A specific bactericidal design strategy was proposed by introducing exogenous metabolites in this study. This strategy was used to optimize two known antibacterial agents, luteolin (M) and Isoprothiolane (D), against Xoo. Based on the prodrug principles, target compound MB and DB were synthesized by combing M or D with exogenous metabolites, respectively. Bactericidal activity test results demonstrated that while the antibacterial ability of target compounds was significantly improved, their selectivity was also well enhanced by the introducing of exogenous metabolites. Comparing with the original compound, the antibacterial activity of target compound was significantly increased 92.0% and 74.5%, respectively. The optimized target compounds were more easily absorbed, and the drug application concentrations were much lower than those of the original agents, which would greatly reduce environmental pollution and relieve resistance risk. Our proposed strategy is of great significance for exploring the specific and selective bactericides against other pathogens.

广谱杀菌剂的广泛和重复使用导致耐药性增加。开发新型广谱杀菌剂不能解决耐药性问题，甚至可能加剧耐药性问题。特异性和选择性杀菌剂的设计已迫在眉睫。通过在本研究中引入外源代谢物，提出了一种特定的杀菌设计策略。该策略用于优化两种已知的抗菌剂木犀草素 (M) 和异丙硫醇 (D)，以对抗Xoo. 根据前药原理，分别将M或D与外源代谢物结合合成目标化合物MB和DB。杀菌活性测试结果表明，在目标化合物的抗菌能力显着提高的同时，通过引入外源性代谢物，其选择性也得到了很好的提高。与原化合物相比，目标化合物的抗菌活性分别显着提高了92.0%和74.5%。优化后的目标化合物更易吸收，用药浓度远低于原药，大大减少环境污染，降低耐药风险。我们提出的策略对于探索针对其他病原体的特异性和选择性杀菌剂具有重要意义。