Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 22, Pages 13669-13679Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01118
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Funding
- National Research Foundation of Korea (NRF) - Korean government [2018R1A2A1A19018526, 2018R1A5A2024425, 2019R1C1C1002128, 2019R1I1A1A01057713]
- 2019 BK21 Plus Project for Medicine, Dentistry and Pharmacy
- International Program of Institute for Protein Research (IPR), Osaka University [ICR-20-05]
- National Research Foundation of Korea [2019R1I1A1A01057713, 2018R1A2A1A19018526, 2019R1C1C1002128] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 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.
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