Hypervirulent Klebsiella pneumoniae (HvKp) is a community-acquired bacterial pathogen that has become the primary cause of monomicrobial liver abscess in Singapore and Asia. HvKp can colonise the gut of healthy individuals, and subsequently translocate to cause systemic infection. As such, factors that facilitate gut carriage of HvKp are important for this pathogen to disseminate in the population. Over 80% of HvKp isolates belong to clonal group 23 (CG23), which is characterised by the presence of a large virulence plasmid as well as two chromosomally integrated mobile genetic elements, genomic island E492 (GIE492) and integrative conjugative element ICEKp10.
We demonstrate that microcin E492 (mccE492), which is produced by GIE492 and colibactin, the synthesis of which is encoded on ICEKp10 are important for HvKp to persist in the gut. MccE492 is a siderophore-microcin that kills other gram-negatives via a trojan horse strategy, while colibactin is a bacterial genotoxin that has been implicated in the development of colorectal cancer. Mutants in the HvKp strain SGH10 which could not produce colibactin, mccE492 or both of these compounds poorly colonised the murine gut relative to wildtype bacteria. Additionally, colonisation of the different mutants also result in a difference in the gut microbiome composition compared to wildtype bacteria.
MccE492 and colibactin enable HvKp to kill E. coli, C. difficile, and other K. pneumoniae and Klebsiella species. We also demonstrate that colibactin causes DNA damage in target bacteria. Under aerobic conditions, colibactin alone does not cause a strong inhibitory effect, but mccE492 and colibactin exhibit synergism in killing competing bacteria. However, under anaerobic conditions, the killing effect of colibactin is as strong as mccE492 alone. Given that pre-treatment with mccE492 sensitises E. coli to colibactin, we hypothesise that microcin increases the permeability of target bacteria to colibactin to enhance killing.
In summary, the acquisition of GIE492 and ICEKp10 allows CG23 HvKp to eliminate competing species via a two-pronged assault of mccE492 and colibactin.