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Emergence of plasmid-mediated high-level tigecycline resistance genes in animals and humans

Abstract

Tigecycline is a last-resort antibiotic that is used to treat severe infections caused by extensively drug-resistant bacteria. tet(X) has been shown to encode a flavin-dependent monooxygenase that modifies tigecycline1,2. Here, we report two unique mobile tigecycline-resistance genes, tet(X3) and tet(X4), in numerous Enterobacteriaceae and Acinetobacter that were isolated from animals, meat for consumption and humans. Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline. Both tet(X3) and tet(X4) increase (by 64–128-fold) the tigecycline minimal inhibitory concentration values for Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. In addition, both Tet(X3) (A. baumannii) and Tet(X4) (E. coli) significantly compromise tigecycline in in vivo infection models. Both tet(X3) and tet(X4) are adjacent to insertion sequence ISVsa3 on their respective conjugative plasmids and confer a mild fitness cost (relative fitness of >0.704). Database mining and retrospective screening analyses confirm that tet(X3) and tet(X4) are globally present in clinical bacteria—even in the same bacteria as blaNDM-1, resulting in resistance to both tigecycline and carbapenems. Our findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.

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Fig. 1: In vivo model confirming the clinical importance of tet(X3) and tet(X4).
Fig. 2: Genetic environment of tet(X3) and tet(X4) in typical plasmids and comparison of the tet(X3)- and tet(X4)-carrying regions.

Data availability

The complete sequences of the tet(X3)- and tet(X4)-carrying plasmids, which support the findings of this study, have been deposited in the NCBI GenBank database under accession numbers MK134375 and MK134376, respectively. Other data that support the findings of this study are presented within this Letter and in the Supplementary Information. Additional data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported in part by grants from the National Key Research and Development Program of China (2018YFD0500300), National Natural Science Foundation of China (81861138051, 81661138002, 31702297, 81871705), Natural Science Foundation of Jiangsu Province (BK20160577), Medical Research Council grant DETER-XDRE-CHINA (MR/P007295/1) and China Agriculture Research System (CARS-36).

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Y.W., T.H., D.L. and J.S. designed the study. T.H., R.Wang, D.L., Y.Lv, Y.S., L.L., Z.Liu, L.W., Y.H., Z.Lv and Q.S. collected the data. T.H., R.Wang, D.L., T.R.W., R.Z., Y.K., Q.J., R.Wei, Z.L., Y.S., G.W., Y.F., H.S., L.S., Y.Li, M.P., Z.S., S.W., G.C., C.W. and J.S. analysed and interpreted the data. Y.W., T.H., D.L. and T.R.W. wrote the manuscript. All authors reviewed, revised, and approved the final report.

Corresponding authors

Correspondence to Jianzhong Shen or Yang Wang.

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Supplementary information

Supplementary Information

Supplementary Figures 1–10 and Supplementary Tables 1–4.

Reporting Summary

Supplementary Table 5

Presence of intact ISVsa3 sequences in various bacterial species.

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He, T., Wang, R., Liu, D. et al. Emergence of plasmid-mediated high-level tigecycline resistance genes in animals and humans. Nat Microbiol 4, 1450–1456 (2019). https://doi.org/10.1038/s41564-019-0445-2

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