The pivotal role of IncFIB(Mar) plasmid in the emergence and spread of hypervirulent carbapenem-resistant Klebsiella pneumoniae

The hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) poses a substantial challenge to the global health care. However, the mechanism behind its evolution and transmission remain elusive. Here, four virulence plasmid types were identified from 310 hv-CRKP isolates collected nationwide during 2017-2018, based on their aerobactin (iuc locus) lineage and IncFIB replicons. Notably, pIUC1-IncFIB(K)₃₇ and pIUC1-IncFIB(Mar), representing two epidemic virulence plasmids in Asia and Europe, respectively, accounted for >90% of the hv-CRKP episodes. Analysis of 494 K. pneumoniae isolates (376 from 2010-2013; 118 from 2017-2018) and 2578 public K. pneumoniae genomes indicated the notable role of IncFIB(Mar) plasmids in the hv-CRKP emergence and spread. Conjugation assays showed the helper IncFIB(Mar) plasmid could efficiently transfer into a hypervirulent strain and uniquely retromobilize with pIUC1-IncFIB(K)₃₇ back into CRKP. Thereafter, the IncFIB(Mar) plasmid either lost rapidly or recombined with pIUC1-IncFIB(K)₃₇, generating the hybrid pIUC1-IncFIB(Mar) plasmid. Our findings elucidated formation, evolution, and dissemination trajectories of the two major hv-CRKP strains in different regions.