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

• DOI: 10.1038/s41564-019-0445-2
• Publication Date: 2019-05-27T16:04:41Z
• Authors: Tao He; Ran Wang; Dejun Liu; Timothy R. Walsh; Rong Zhang; Yuan Lv; Yuebin Ke; Quanjiang Ji; Ruicheng Wei; Zhihai Liu; Yingbo Shen; Gang Wang; Lichang Sun; Lei Lei; Ziquan Lv; Yun Li; Maoda Pang; Liyuan Wang; Qiaoling Sun; Yulin Fu; Huangwei Song; Yuxin Hao; Zhangqi Shen; Shaolin Wang; Gongxiang Chen; Congming Wu; Jianzhong Shen; Yang Wang
• Keywords: 0301 basic medicine; Meat; Bacteria; Tetracycline Resistance; Microbial Sensitivity Tests; Tigecycline; Anti-Bacterial Agents; Mixed Function Oxygenases; 3. Good health; 03 medical and health sciences; Bacterial Proteins; DNA Transposable Elements; Animals; Humans; Plasmids

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.