Emergence of a Novel Plasmid-Mediated Tigecycline Resistance Gene Cluster, tmexCD4-toprJ4, in Klebsiella quasipneumoniae and Enterobacter roggenkampii

The occurrence of transferable tigecycline resistance determinants, tmexCD1-toprJ1, tmexCD2-toprJ2, tmexCD3-toprJ1b, and multiple tet(A) and tet(X) variants, presents an unprecedented challenge to clinical therapeutic options. tmexCD-toprJ-like gene clusters can mediate multidrug resistance and have been detected in a variety of bacteria. Here, we characterized the fourth tmexCD-toprJ-like gene cluster, tmexCD4-toprJ4, identified on untypeable plasmids of Klebsiella quasipneumoniae and Enterobacter roggenkampii isolated from chicken meat and environmental samples from farm markets, respectively. TMexCD4-TOprJ4 was closely related (92 to 99% amino acid identity) to TMexCD1-TOprJ1, TMexCD2-TOprJ2, and TMexCD3-TOprJ1. Phylogenetic analysis revealed that tmexCD4-toprJ4 was not in the same branch as the other three variants. Expression of tmexCD4-toprJ4 increased tigecycline efflux in Escherichia coli and resulted in a 4- to 8-fold increase in MICs of tigecycline in E. coli and Klebsiella pneumoniae. Moreover, tmexCD4-toprJ4 can act synergistically with its upstream gene tet(A) to reduce the susceptibility of E. coli and K. pneumoniae strains to tigecycline. The tmexCD4-toprJ4-containing plasmid is a novel plasmid type and can be transferred to E. coli and K. pneumoniae only via electrotransformation. The increasing emergence of plasmid-mediated tigecycline resistance gene clusters suggests that the spread of tmexCD-toprJ-like gene clusters requires widespread attention. IMPORTANCE The plasmid-mediated tigecycline resistance gene cluster tmexCD1-toprJ1 and other variants have been detected in a variety of strains from multiple sources, including human-derived strains. In addition to tigecycline, these tmexCD-toprJ-like gene clusters reduce susceptibility of the host strain to many other antimicrobials. Here, we identified tmexCD4-toprJ4 in K. quasipneumoniae and E. roggenkampii, suggesting that this gene cluster is already present in the human-associated environment and the risk of transmission to humans is increased. Monitoring tigecycline-resistant Gram-negative bacteria is essential for understanding and addressing the spread of this gene cluster in agriculture and health care.

Automated summary

A newly identified transferable plasmid-mediated tigecycline resistance gene cluster, tmexCD4-toprJ4, was found in Klebsiella quasipneumoniae and Enterobacter roggenkampii isolated from chicken meat and environmental samples. The gene cluster can increase bacterial resistance to tigecycline and is different from other variants. It can also synergistically reduce susceptibility to tigecycline in combination with other genes.