Structural and Functional Study of the Klebsiella pneumoniae VapBC Toxin-Antitoxin System, Including the Development of an Inhibitor That Activates VapC
Structural and Functional Study of the Klebsiella pneumoniae VapBC Toxin-Antitoxin System, Including the Development of an Inhibitor That Activates VapC
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DOI：
10.1021/acs.jmedchem.0c01118
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发表时间：
2020-11-25
影响因子：
7.3
通讯作者：
Lee, Bong-Jin
中科院分区：
文献类型：
--
作者：
Kang, Sung-Min;Jin, Chenglong;Lee, Bong-Jin
肺炎克雷伯菌是最重要的条件致病菌之一。TA系统是很有希望的药物靶点，因为它们与细菌病原体的存活有关。然而，关于肺炎克雷伯菌TA系统的结构信息仍然缺乏；因此，有必要对这些信息进行探索，以开发抗菌药物。在这里，我们以2.00埃的分辨率展示了肺炎克雷伯菌VapBC复合物的第一个晶体结构。我们通过Mg2+开关确定了VapB抗毒素的毒素抑制机制，其中Mg2+被VapB的R79取代。这种活性部位的抑制机制是一个新发现，也是第一个在细菌TA系统中被确定的。此外，还发现并研究了激活VapC毒素的抑制剂，包括肽和小分子。这些抑制剂可以通过破坏VapBC复合体并激活VapC而起到抗菌作用。我们对肺炎克雷伯菌VapBC系统的全面研究将有助于阐明VapBC系统中尚未解决的难题，并开发潜在的抗菌药物。
Klebsiella pneumoniae is one of the most critical opportunistic pathogens. TA systems are promising drug targets because they are related to the survival of bacterial pathogens. However, structural information on TA systems in K. pneumoniae remains lacking; therefore, it is necessary to explore this information for the development of antibacterial agents. Here, we present the first crystal structure of the VapBC complex from K. pneumoniae at a resolution of 2.00 angstrom. We determined the toxin inhibitory mechanism of the VapB antitoxin through an Mg2+ switch, in which Mg2+ is displaced by R79 of VapB. This inhibitory mechanism of the active site is a novel finding and the first to be identified in a bacterial TA system. Furthermore, inhibitors, including peptides and small molecules, that activate the VapC toxin were discovered and investigated. These inhibitors can act as antimicrobial agents by disrupting the VapBC complex and activating VapC. Our comprehensive investigation of the K. pneumoniae VapBC system will help elucidate an unsolved conundrum in VapBC systems and develop potential antimicrobial agents.