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Authors: He, Tao and Wang, Ran and Liu, Dejun and Walsh, Timothy R and Zhang, Rong and Lv, Yuan and Ke, Yuebin and Ji, Quanjiang and Wei, Ruicheng and Liu, Zhihai and Shen, Yingbo and Wang, Gang and Sun, Lichang and Lei, Lei and Lv, Ziquan and Li, Yun and Pang, Maoda and Wang, Liyuan and Sun, Qiaoling and Fu, Yulin and Song, Huangwei and Hao, Yuxin and Shen, Zhangqi and Wang, Shaolin and Chen, Gongxiang and Wu, Congming and Shen, Jianzhong and Wang, Yang

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.

Journal: Nature microbiology
DOI: 10.1038/s41564-019-0445-2
Year: 2019

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