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

Abstract

The occurrence of transferable tigecycline resistance determinants, <i>tmexCD1-toprJ1</i>, <i>tmexCD2-toprJ2</i>, <i>tmexCD3-toprJ1b</i>, and multiple <i>tet</i>(A) and <i>tet</i>(X) variants, presents an unprecedented challenge to clinical therapeutic options. <i>tmexCD-toprJ</i>-like gene clusters can mediate multidrug resistance and have been detected in a variety of bacteria. Here, we characterized the fourth <i>tmexCD-toprJ</i>-like gene cluster, <i>tmexCD4-toprJ4</i>, 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 <i>tmexCD4-toprJ4</i> was not in the same branch as the other three variants. Expression of <i>tmexCD4-toprJ4</i> 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, <i>tmexCD4-toprJ4</i> can act synergistically with its upstream gene <i>tet</i>(A) to reduce the susceptibility of E. coli and K. pneumoniae strains to tigecycline. The <i>tmexCD4-toprJ4-</i>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 <i>tmexCD-toprJ</i>-like gene clusters requires widespread attention. <b>IMPORTANCE</b> The plasmid-mediated tigecycline resistance gene cluster <i>tmexCD1-toprJ1</i> and other variants have been detected in a variety of strains from multiple sources, including human-derived strains. In addition to tigecycline, these <i>tmexCD-toprJ</i>-like gene clusters reduce susceptibility of the host strain to many other antimicrobials. Here, we identified <i>tmexCD4-toprJ4</i> in <i>K. quasipneumoniae</i> and <i>E. roggenkampii</i>, 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.