Co-existence of a novel plasmid-mediated efflux pump with colistin resistance gene mcr in one plasmid confers transferable multidrug resistance in Klebsiella pneumoniae

Tigecycline is considered one of the last-resort antimicrobials for carbapenem-resistant K. pneumoniae. Plasmid-mediated tigecycline resistance remains largely unclear. Here, by utilizing whole genome sequencing, we report a plasmid-mediated tigecycline resistance mechanism, a 6,489 bp Resistance-nodulation-division family (RND) efflux pump (tmexCD1-toprJ1 pump), that confers transferable tigecycline resistance in K pneumoniae isolated from patients and chickens. In addition, we identified high prevalence of the plasmids co-harbouring both tmexCD1-toprJ1 pump and mcr (tmexCD1-mcr co-harbouring plasmid) from human in our nationwide collection. Even worse, the tmexCD1-toprJ1 and mcr co-harbouring plasmid was also co-existed with bla(NDM)-harbouring IncX3 plasmid in the same host, resulting in pandrug resistance. Phylogenetic analysis suggested that the plasmid-borne tmexCD1-toprJ1 originated from the chromosome of Aeromonas spp. through Tn5393-mediating translocation. Both plasmid-harbored tmexCD1-toprJ1 gene and mcr-8 likely originated from animal isolates and then spread to human. Our findings highlight a substantial threat of tmexCD1-toprJ1-mcr8 co-harbouring IncFIA/IncFII plasmid to public health due to their mobile resistance to both tigecycline and colistin, emphasizing an urgent need for further global surveillance on this plasmid.