在代谢途径中寻找新的药物靶点的研究集中于细菌对外源物质的摄取和分解的特殊机制。在铜绿假单胞菌PAO1代谢外源2,3-丁二醇并影响致病性的机理研究中，申请者发现该菌株2,3-丁二醇下游代谢依赖于L-苹果酸醌氧化还原酶MqoB。MqoB与人类L-苹果酸脱氢酶存在显著区别，是PAO1中心代谢途径特殊关键酶。MqoB突变菌株表现出乙酸积累的代谢表型与绿脓菌素降低的毒力表型，MqoB抑制剂阿魏醇可降低PAO1的绿脓菌素产生。基于转录组分析与部分前期结果，申请者提出了MqoB敲除递次引起PAO1中乙酸利用阻断、中心代谢受限、脂肪酸代谢紊乱、群体感应信号分子PQS降低与绿脓菌素下降的理论假设。本项目旨在验证该假设，确定MqoB在PAO1乙酸利用与绿脓菌素产生中的作用，分析阿魏醇对PAO1毒力因子产生、致病力的影响，研究结果将为靶向致病菌的中心代谢途径特殊关键酶设计药物分子、解决细菌耐药问题奠定理论基础。

The search for novel drug targets in metabolic pathways has focused on the specific mechanisms of bacterial uptake and degradation of exogenous substances. In the research of exogenous 2,3-butanediol metabolism and its influence on pathogenicity of Pseudomonas aeruginosa PAO1, the applicant found that the downstream metabolism of 2,3-butanediol relies on L-malate quinone oxidoreductase MqoB. MqoB is significantly different from human L-malate dehydrogenase, and is a special key enzyme of P. aeruginosa PAO1 central metabolic pathway. The MqoB mutant strain of P. aeruginosa showed the metabolic phenotype of acetate accumulation and virulence phenotype of decreased pyocyanin production. The MqoB inhibitor ferulenol can reduce the pyocyanin production of P. aeruginosa PAO1. Based on the transcriptome analysis and preliminary results, the applicant proposed the theoretical hypothesis that the knockout of MqoB would sequentially cause the blocking of acetate utilization, the restriction of central metabolism, the disorder of fatty acid metabolism, the decrease of quorum sensing signal molecule PQS and finally the reduction of pyocyanin in P. aeruginosa PAO1. This project aims to verify this hypothesis, determine the role of MqoB in the utilization of acetate and the production of pyocyanin, and analyze the influence of ferulenol on the production of virulence factor and pathogenicity of P. aeruginosa PAO1. The research results will lay a theoretical foundation for the design of drug molecules targeting at the special key enzymes of the central metabolic pathway of pathogenic bacteria and the solution of the problem of bacterial drug resistance.