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      Plasmid-mediated tigecycline-resistant gene tet(X4) in Escherichia coli from food-producing animals, China, 2008–2018

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          ABSTRACT

          The recent emergence of plasmid-mediated tigecycline resistance genes, tet(X3) and tet(X4), in animals and humans in China would pose a foreseeable threat to public health. To illustrate this paradigm shift in tigecycline resistance, here, covering the period 2008-2018, we retrospectively analysed a national strain collection of Escherichia coli (n = 2254), obtained from chickens and pigs, in six representative provinces of China. The gene tet(X4) was identified in five pig isolates collected in 2016 and 2018 from the provinces of Sichuan (3/15, 2018), Henan (1/25, 2018) and Guangdong (1/28, 2016), but not in the isolates prior to 2016. None of the isolates was detected harbouring tet(X3). All tet(X4)-positive E. coli exhibited high levels of tigecycline resistance (MICs, 16-64 mg/L), and two were confirmed as colistin resistant, harbouring chromosome-borne mcr-1 gene. The gene tet(X4) was detected on a plasmid in all five isolates, whereas a co-location of tet(X4) on the chromosome of one isolate was observed. Diverse host strains and novel plasmids related to the tet(X4) gene were observed. Our timely findings of the recent emergence of tet(X4) gene in food animal support the rapid surveillance and eradication of this gene before it is established.

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

          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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            Towards Understanding MCR-like Colistin Resistance

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

              Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) 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 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.
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                Author and article information

                Journal
                Emerg Microbes Infect
                Emerg Microbes Infect
                TEMI
                temi20
                Emerging Microbes & Infections
                Taylor & Francis
                2222-1751
                2019
                21 October 2019
                : 8
                : 1
                : 1524-1527
                Affiliations
                [a ]Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University , Beijing, People’s Republic of China
                [b ]China Institute of Veterinary Drug Control , Beijing, People’s Republic of China
                Author notes
                [CONTACT ] Shixin Xu 1559757434@ 123456qq.com China Institute of Veterinary Drug Control , No. 8, Zhongguancun South St., Haidian District, Beijing 100081, People’s Republic of China
                Congming Wu wucm@ 123456cau.edu.cn Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University , No. 2, Yuanmingyuan West Rd., Haidian District, Beijing 100193, People’s Republic of China
                [*]

                These authors contributed equally to this work.

                Supplemental data for this article can be accessed at https://doi.org/10.1080/22221751.2019.1678367.

                Article
                1678367
                10.1080/22221751.2019.1678367
                6818123
                31631781
                1ff99100-93a2-4cfa-86f2-4950355e7472
                © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 July 2019
                : 25 September 2019
                : 01 October 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 15, Pages: 4
                Funding
                Funded by: National Key Research and Development Program of China 10.13039/501100012166
                Award ID: 2018YFD0500300
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81861138051
                Award ID: 81661138002
                This work was supported in part by the National Key Research and Development Program of China [grant number 2018YFD0500300] and the National Natural Science Foundation of China [grant numbers 81861138051 and 81661138002].
                Categories
                Letter

                mobile tigecycline resistance,escherichia coli,food-producing animals,retrospective analysis,china

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