Emergence of a plasmid-borne tigecycline resistance in Klebsiella pneumoniae in Vietnam

Abstract

Tigecycline is a last-resort antimicrobial used to treat multidrug-resistant Gram-negative bacterial infections. One of the common antimicrobial resistance mechanisms is the efflux pump system composed of membrane protein complexes to excrete xenobiotic substrates. Recently, a novel gene cluster, tmexCD1-toprJ1, encoding the resistance–nodulation–cell division (RND) efflux pump was identified on plasmids in Klebsiella pneumoniae isolates in China. TMexCD1-TOprJ1 was found to be capable of excreting multiple antimicrobials, including tigecycline, which contributed to the strain's resistance. In this study, we identified K. pneumoniae isolates harbouring the tmexCD1-toprJ1 genes outside of China for the first time. Two tigecycline-resistant K. pneumoniae isolates belonging to ST273 by multilocus sequence typing were collected from different patients in a medical institution in Hanoi, Vietnam, in 2015. Whole-genome sequence analysis revealed that these isolates harboured a 288.0 kb tmexCD1-toprJ1–carrying plasmid with IncFIB and IncHI1B replicons. The tmexCD1-toprJ1 gene cluster was surrounded by several mobile gene elements, including IS26, and the plasmids had high sequence identity with that of K. pneumoniae isolated in China. Our finding suggests that the horizontal spread of tigecycline resistance mediated by tmexCD1-toprJ1–carrying plasmids has occurred in Vietnam and other countries, and raises concern about the further global dissemination.

A transferable IncC-IncX3 hybrid plasmid co-carrying blaNDM-4, tet(X4), and tmexCD3-toprJ3 confers resistance to carbapenem and tigecycline

“…Recently, mobile tigecycline resistance genes, tet(X3), tet(X4), and other variants, tet(X5) to tet(X14), encoding flavin-dependent monooxygenases that catalyze tigecycline degradation were emerged in Enterobacterales and Acinetobacter species in China and other countries[4][5][6] . Furthermore, a mobile tigecycline resistance gene cluster, tmexCD-toprJ, encoding the resistancenodulation-cell division (RND) efflux pump that excretes multiple antimicrobials, such as tetracyclines including tigecycline, cephalosporins, fluoroquinolones, and aminoglycosides, emerged predominantly in Enterobacterales: tmexCD1-toprJ1 was identified in plasmids in Klebsiella species isolated from humans and livestock in China and Vietnam[7][8][9] . tmexCD2-toprJ2 was identified in the plasmid and chromosome of Raoultella ornithinolytica isolated from a human in China 10 .A carbapenem-and tigecycline-resistant K. aerogenes isolate NUITM-VK5 was obtained from an urban drainage in Hanoi, Vietnam, in March 2021.…”

A Transferable IncC-IncX3 Hybrid Plasmid Cocarrying bla NDM-4 , tet (X), and tmexCD3-toprJ3 Confers Resistance to Carbapenem and Tigecycline

“…FN396876 ) and tet (X) (accession no. MK134376 ) and purified genomic DNA from tmexCD1-toprJ1 -harboring Klebsiella pneumoniae strain MH15-269M ( 9 ) were used as positive controls. Purified water was used as a negative control.…”

“…Recently, variants of a mobile tigecycline resistance gene, tet (X), encoding flavin-dependent monooxygenases that catalyze tigecycline degradation, emerged in Enterobacterales and Acinetobacter species in China and other countries ( 4 – 6 ). Furthermore, a mobile tigecycline resistance gene cluster, tmexCD-toprJ , encoding the resistance-nodulation-cell division (RND) efflux pump that excretes multiple antimicrobials, such as tetracyclines including tigecycline, cephalosporins, fluoroquinolones, and aminoglycosides, emerged predominantly in Enterobacterales : tmexCD1-toprJ1 was identified in plasmids in Klebsiella species isolated from humans and livestock in China and Vietnam ( 7 – 9 ). tmexCD2-toprJ2 was identified in the plasmid and chromosome of Raoultella ornithinolytica isolated from a human in China ( 10 ).…”

Characterization of IncHI1B Plasmids Encoding Efflux Pump TmexCD2-ToprJ2 in Carbapenem-Resistant Klebsiella variicola, Klebsiella quasipneumoniae, and Klebsiella michiganensis Strains

“…This gene cluster was first identified in animal isolates but soon later was also found in clinical isolates (Sun et al, 2020). TmexCD1-ToprJ1 was initially reported in China, but it has now been found in clinical K. pneumoniae isolates outside of China (Hirabayashi et al, 2021), suggesting this resistance has started to spread into other global regions. Two homologous variants, TmexCD2-ToprJ2 (Wang et al, 2021a) and TmexCD3-ToprJ3 (Wang et al, 2021b), have also been identified in Raoultella ornithinolytica and Proteus mirabilis, displaying similar tigecycline resistance profiles.…”