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

Nature Microbiology volume 4, pages 1450–1456 (2019)Cite this article

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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.

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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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Author notes

  1. These authors contributed equally: Tao He, Ran Wang, Dejun Liu.

Authors and Affiliations

  1. Key Laboratory for Control Technology and Standard for Agro-product Safety and Quality, Ministry of Agriculture and Rural Affairs, Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing, China

    Tao He, Ran Wang, Ruicheng Wei, Gang Wang, Lichang Sun & Maoda Pang

  2. Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China

    Dejun Liu, Timothy R. Walsh, Zhihai Liu, Yingbo Shen, Lei Lei, Yulin Fu, Huangwei Song, Yuxin Hao, Zhangqi Shen, Shaolin Wang, Congming Wu, Jianzhong Shen & Yang Wang

  3. Department of Medical Microbiology and Infectious Disease, Institute of Infection and Immunity, Cardiff, UK

    Timothy R. Walsh

  4. The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China

    Rong Zhang, Qiaoling Sun & Gongxiang Chen

  5. Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China

    Yuan Lv, Yun Li & Liyuan Wang

  6. Key Laboratory of Molecular Epidemiology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

    Yuebin Ke & Ziquan Lv

  7. School of Physical Science and Technology, ShanghaiTech University, Shanghai, China

    Quanjiang Ji

  8. Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China

    Jianzhong Shen & Yang Wang

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  1. Tao He
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Contributions

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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