Kabongo Augustin Tshibaka, Acharjee Rajib, Sakura Takaya, Bundutidi Gloria Mavinga, Hartuti Endah Dwi, Davies Cadi, Gundogdu Ozan, Kita Kiyoshi, Shiba Tomoo, Inaoka Daniel Ken
School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
Front Mol Biosci. 2023 Jan 26;10:1095026. doi: 10.3389/fmolb.2023.1095026. eCollection 2023.
infection poses a serious global threat to public health. The increasing incidence and antibiotic resistance of this bacterial infection have necessitated the adoption of various strategies to curb this trend, primarily through developing new drugs with new mechanisms of action. The enzyme malate:quinone oxidoreductase (MQO) has been shown to be essential for the survival of several bacteria and parasites. MQO is a peripheral membrane protein that catalyses the oxidation of malate to oxaloacetate, a crucial step in the tricarboxylic acid cycle. In addition, MQO is involved in the reduction of the quinone pool in the electron transport chain and thus contributes to cellular bioenergetics. The enzyme is an attractive drug target as it is not conserved in mammals. As a preliminary step in assessing the potential application of MQO from (CjMQO) as a new drug target, we purified active recombinant CjMQO and conducted, for the first time, biochemical analyses of MQO from a pathogenic bacterium. Our study showed that ferulenol, a submicromolar mitochondrial MQO inhibitor, and embelin are nanomolar inhibitors of CjMQO. We showed that both inhibitors are mixed-type inhibitors malate and noncompetitive quinone, suggesting the existence of a third binding site to accommodate these inhibitors; indeed, such a trait appears to be conserved between mitochondrial and bacterial MQOs. Interestingly, ferulenol and embelin also inhibit the growth of , supporting the hypothesis that MQO is essential for survival and is therefore an important drug target.
感染对全球公共卫生构成严重威胁。这种细菌感染发病率的上升和抗生素耐药性的出现，使得必须采取各种策略来遏制这一趋势，主要是通过开发具有新作用机制的新药。苹果酸：醌氧化还原酶（MQO）已被证明对几种细菌和寄生虫的生存至关重要。MQO是一种外周膜蛋白，催化苹果酸氧化为草酰乙酸，这是三羧酸循环中的关键一步。此外，MQO参与电子传递链中醌池的还原，从而有助于细胞生物能学。由于该酶在哺乳动物中不保守，因此是一个有吸引力的药物靶点。作为评估来自[具体名称未给出]（CjMQO）的MQO作为新药物靶点潜在应用的初步步骤，我们纯化了活性重组CjMQO，并首次对一种致病细菌的MQO进行了生化分析。我们的研究表明，亚微摩尔浓度的线粒体MQO抑制剂阿魏酸和纳摩尔浓度的紫铆因是CjMQO的抑制剂。我们表明这两种抑制剂都是对苹果酸为混合型抑制、对醌为非竞争性抑制，这表明存在第三个结合位点来容纳这些抑制剂；事实上，这种特性似乎在线粒体和细菌的MQO之间是保守的。有趣的是，阿魏酸和紫铆因也抑制[具体细菌名称未给出]的生长，支持了MQO对[具体细菌名称未给出]生存至关重要且因此是一个重要药物靶点的假设。
