Letter | Published:

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 Gram-negative and Gram-positive bacteria1. Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection2,3. Here, we report the emergence of the 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 US FDA newly approved eravacycline. The tet(X4)-harbouring 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-harbouring 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 various ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.

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Data availability

The whole-genome sequencing data of E.coli LHM10-1 and G3X16-2 strains have been submitted to the NCBI under the BioSample accession number SAMN11087649 and SAMN11180601, respectively. Extra data supporting the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

This work was jointly supported by the National Key Research and Development Program of China (2016YFD0501300), the Program for Innovative Research Team in the University of Ministry of Education of China (IRT_17R39), and the Foundation for Innovation and Strengthening School Project of Guangdong, China (2016KCXTD010). L.C. and B.N.K. receive support from the US National Institutes of Health grants (R21AI117338, R01AI090155 and R21AI135250).

Author information

J.S. and C.C. contributed equally in this study. Y.-H.L., L.C., X.-P.L. and J.S. designed the study. C.C., C.-Y.C., Y.Z., X.L., Z.-H.C., X.-Y.M., K.-X.Z., H.-M.L., Z.-H.Z., S.-D.Z., J.-N.L., H.D., B.H. and F.-Y.Y. collected the data. J.S., C.C., Y.F., L.-X.F., X.-L.L., R.-M.Z. and Y.-Z.T. analysed and interpreted the data. Y.-H.L., B.M., B.N.K., L.C., J.S., X.-P.L. and C.C. wrote the draft of the manuscript. All authors reviewed, revised and approved the final report.

Correspondence to Xiao-Ping Liao or Liang Chen or Ya-Hong Liu.

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Fig. 1: Map of tet(X4) sampling areas in China.
Fig. 2: The activity of Tet(X4) on tetracyclines in vitro and in vivo.
Fig. 3: Characteristics of the IncQ1 tet(X4)-harbouring plasmid pLHM10-1-p6.
Fig. 4: PFGE-XbaI dendrogram and details about tet(X4)-positive E.coli isolates.