Global emergence of Carbapenem-resistant Hypervirulent Klebsiella pneumoniae driven by an IncFIIK34 KPC-2 plasmid
Jianping Jiang, Leilei Wang, Yiyi Hu, Xin Chen, Pei Li, Jianfeng Zhang, Yixin Zhang, Jiachun Su, Xiaogang Xu, Yonghong Xiao, Zhengyin Liu, Yunsong Yu, Hainv Gao, Yohei Doi, David van Duin, Vance G. Fowler, Liang Chen, Minggui Wang
Abstract
Background Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) has been increasingly reported worldwide, posing a severe challenge to public health; however, the mechanisms driving its emergence and global dissemination remain unclear. Methods We analysed CR-hvKp strains derived from canonical hvKp backgrounds, and acquired a carbapenemase-encoding gene. These strains were identified from 485 CRKp isolates in the CRACKLE-2 China cohort, 259 CRKp isolates from a multi-centre study, and 67,631 K. pneumoniae genomes available in GenBank. Clinical isolates harbouring the IncFII K34 KPC-2 plasmid were selected for genome sequencing, RNA-Seq, conjugation assays, in vivo, ex vivo, and in vitro phenotypic characterisation. Findings Analysis of clinical CR-hvKp isolates and the 414 genomes from 24 countries available in GenBank identified an IncFII K34 KPC-2 plasmid as the prevalent KPC plasmid (detected in 25%, 45/178 of KPC-producing CR-hvKp). Compared with the epidemic IncFII K2 KPC-2 plasmid, the IncFII K34 KPC-2 plasmid exhibited a 100- to 1000-fold increase in conjugation frequency (10 −4 –10 −5 vs. 10 −7 ) and an in vitro growth advantage under meropenem challenge–likely due to the overexpression of conjugation-related genes and an increased bla KPC copy number and expression. CR-hvKp isolates and hvKp transconjugants carrying this plasmid often exhibited reduced mucoviscosity, while retaining hypervirulence in both murine models and human neutrophil assays. Interpretation The IncFII K34 plasmid may be a key factor driving the global dissemination of CR-hvKp, underscoring the urgent need for enhanced molecular surveillance of this emerging pathogen. Funding National Natural Science Foundation of China and National Institutes of Health.