Plasmid-encoded tet(X) genes that confer high-level tigecycline resistance in Escherichia coli

Abstract

Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria 1 . Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection 2 , 3 . Here we report the emergence of plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the FDA newly approved eravacycline. The tet (X4)-harboring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet (X4)-positive E. coli strains, including isolates co-harboring mcr-1 , have been widely detected in pigs, chickens, soil, and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into a variety of ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.

Emergence of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump Conferring Resistance to Multiple Drugs, Including Tigecycline, in Klebsiella pneumoniae

“…Tigecycline has not been used in veterinary clinics; however, selective pressure imposed by heavy use of older tetracyclines (doxycycline, chlortetracycline, and oxytetracycline) and other antimicrobials (enrofloxacin, florfenicol, and cephalosporins) in China could have contributed to the emergence of this multisubstrate efflux pump (47). The broad substrate spectrum might also explain why the prevalence rates for TMexCD1-TOprJ1-producing Enterobacteriaceae in animal-associated samples are higher than the rates reported for tet(X3) and tet(X4), which specifically confer tetracycline resistance (20,21).…”

“…In addition to chromosomal mechanisms, mutations in the plasmid-borne tetracycline efflux pump gene tet(A) reportedly contribute to tigecycline resistance (19). Very recently, plasmid-borne genes tet(X3), tet(X4), and tet(X5), encoding the tigecycline modification enzymes, were reported in Acinetobacter baumannii and Enterobacteriaceae from China (20)(21)(22).…”

In vitro Activity of Apramycin Against Carbapenem-Resistant and Hypervirulent Klebsiella pneumoniae Isolates

“…In this study no CR-hvKp isolates were found to be resistant to the "last resort" antimicrobial agents, including ceftazidimeavibactam, colistin and tigecycline, however, the treatment arsenal for CR-hvKp could be easily compromised by the spread of mobile resistant genes. Plasmid-mediated colistin and tigecycline resistance mechanisms, MCR-1 and Tet(x), have been described in China (Liu et al, 2016;He et al, 2019;Sun et al, 2019). In addition, the FDA approved cefetazidime-avibactam is ineffective against metallo-β-lactamase (e.g., NDM) producers.…”

Critical analysis of antibacterial agents in clinical development

“…Lately, enzymatic degradation has gained more attention, as new, highly transferrable plasmid mediated tetracycline inactivating enzymes, Tet(X3) and Tet(X4), have been described and are glob ally present. They degrade all tetracyclines, including tigecycline and the recently approved eravacycline and omadacycline [77][78][79] . Such plasmids may carry other resist ance determinants, such as mcr1 (colistin resistance) and genes encoding MBLs (for example, NDM), thus poten tially rendering isolates XDR 78,80 .…”

“…They degrade all tetracyclines, including tigecycline and the recently approved eravacycline and omadacycline [77][78][79] . Such plasmids may carry other resist ance determinants, such as mcr1 (colistin resistance) and genes encoding MBLs (for example, NDM), thus poten tially rendering isolates XDR 78,80 . The fully synthetic eravacycline (intravenous) has activity against CRE comparable to tigecycline and exhibits cross resistance with tigecycline 79,81 .…”