Structural and Functional Study of the Klebsiella pneumoniae VapBC Toxin–Antitoxin System, Including the Development of an Inhibitor That Activates VapC

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 Å. 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.