- 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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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 ?. 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.
- Kang, Sung-Min,Jin, Chenglong,Kim, Do-Hee,Lee, Yuno,Lee, Bong-Jin
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p. 13669 - 13679
(2020/12/02)
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- Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR- and XDR-MTB
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A high-throughput screening effort on 45,000 compounds resulted in the discovery of a disubstituted oxazole as a new structural class inhibitor of Mycobacterium tuberculosis (Mtb). In order to improve the activity and investigate the SAR of this scaffold, a series of disubstituted azole analogues have been designed and synthesized. The newly synthesized compounds 1a-y were evaluated for their in vitro anti-TB activity versus replicating, multi- and extensive drug resistant Mtb strains. All the compounds, except 1o, 1p and 1q, showed potent anti-TB activity with MIC of 1-64 mg/L. The test of broad spectrum panel revealed that this series are specific to Mtb. The cytotoxicity assessment indicated that the compounds were not cytotoxic against HEK 293 cells. The compounds could have a novel mechanism to anti-Mtb as they can inhibit drug sensitive and drug resistant Mtb.
- Li, Dongsheng,Gao, Nana,Zhu, Ningyu,Lin, Yuan,Li, Yan,Chen, Minghua,You, Xuefu,Lu, Yu,Wan, Kanglin,Jiang, Jian-Dong,Jiang, Wei,Si, Shuyi
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p. 5178 - 5181
(2015/11/09)
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- Benzoylpiperidylalkylindoles
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New benzoylpiperidylalkylindoles and related compounds possessing tranquilizing, anti-hypertensive and analgesic properties and a process for the preparation thereof are described.
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