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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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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Forsberg, K. J., Patel, S., Wencewicz, T. A. & Dantas, G. The tetracycline destructases: a novel family of tetracycline-inactivating enzymes. Chem. Biol. 22, 888–897 (2015).
Moore, I. F., Hughes, D. W. & Wright, G. D. Tigecycline is modified by the flavin-dependent monooxygenase TetX. Biochemistry 44, 11829–11835 (2005).
Laxminarayan, R., Sridhar, D., Blaser, M., Wang, M. & Woolhouse, M. Achieving global targets for antimicrobial resistance. Science 353, 874–875 (2016).
Karageorgopoulos, D. E. & Falagas, M. E. Current control and treatment of multidrug-resistant Acinetobacter baumannii infections. Lancet Infect. Dis. 8, 751–762 (2008).
Rodríguez-Baño, J., Gutiérrez-Gutiérrez, B., Machuca, I. & Pascual, A. Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing Enterobacteriaceae. Clin. Microbiol. Rev. 31, e00079-17 (2018).
Liu, Y. Y. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16, 161–168 (2016).
Partridge, S. R. et al. Proposal for assignment of allele numbers for mobile colistin resistance (mcr) genes. J. Antimicrob. Chemother. 73, 2625–2630 (2018).
Tasina, E., Haidich, A. B., Kokkali, S. & Arvanitidou, M. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect. Dis. 11, 834–844 (2011).
Brust, K., Evans, A. & Plemmons, R. Favourable outcome in the treatment of carbapenem-resistant Enterobacteriaceae urinary tract infection with high-dose tigecycline. J. Antimicrob. Chemother. 69, 2875–2876 (2014).
Marchaim, D. et al. Major variation in MICs of tigecycline in Gram-negative bacilli as a function of testing method. J. Clin. Microbiol. 52, 1617–1621 (2014).
Babinchak, T., Ellis-Grosse, E., Dartois, N., Rose, G. M. & Loh, E. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin. Infect. Dis. 41, S354–S367 (2005).
Ellis-Grosse, E. J., Babinchak, T., Dartois, N., Rose, G. & Loh, E. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin. Infect. Dis. 41, S341–S353 (2005).
Sun, Y. et al. The emergence of clinical resistance to tigecycline. Int J. Antimicrob. Agents 41, 110–116 (2013).
Du, X. et al. The rapid emergence of tigecycline resistance in bla KPC-2 harboring Klebsiella pneumoniae, as mediated in vivo by mutation in tetA during tigecycline treatment. Front. Microbiol. 9, 648 (2018).
Yao, H., Qin, S., Chen, S., Shen, J. & Du, X. D. Emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae. Lancet Infect. Dis. 18, 25 (2018).
Yang, W. et al. TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J. Biol. Chem. 279, 52346–52352 (2004).
Deng, M. et al. Molecular epidemiology and mechanisms of tigecycline resistance in clinical isolates of Acinetobacter baumannii from a Chinese university hospital. Antimicrob. Agents Chemother. 58, 297–303 (2014).
Leski, T. A. et al. Multidrug-resistant tet(X)-containing hospital isolates in Sierra Leone. Int J. Antimicrob. Agents 42, 83–86 (2013).
Eitel, Z., Sóki, J., Urbán, E. & Nagy, E. The prevalence of antibiotic resistance genes in Bacteroides fragilis group strains isolated in different European countries. Anaerobe 21, 43–49 (2013).
Pehrsson, E. C. et al. Interconnected microbiomes and resistomes in low-income human habitats. Nature 533, 212–216 (2016).
Guiney, D. G. Jr., Hasegawa, P. & Davis, C. E. Expression in Escherichia coli of cryptic tetracycline resistance genes from Bacteroides R plasmids. Plasmid 11, 248–252 (1984).
Tanaka, S. K., Steenbergen, J. & Villano, S. Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. Bioorg. Med. Chem. 24, 6409–6419 (2016).
Sutcliffe, J. A., O’Brien, W., Fyfe, C. & Grossman, T. H. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob. Agents Chemother. 57, 5548–5558 (2013).
Volkers, G., Palm, G. J., Weiss, M. S., Wright, G. D. & Hinrichs, W. Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase. FEBS Lett. 585, 1061–1066 (2011).
Personal Care Product Market Development Analysis (China Industry Research Net, 2018); http://www.chinairn.com/report/20180208/093004908.html
Volkers, G. et al. Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX. Acta Crystallogr D 69, 1758–1767 (2013).
Petkovic, S. & Hinrichs, W. Antibiotic resistance: blocking tetracycline destruction. Nat. Chem. Biol. 13, 694–695 (2017).
Park, J. et al. Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes. Nat. Chem. Biol. 13, 730–736 (2017).
Van Boeckel, T. P. et al. Global trends in antimicrobial use in food animals. Proc. Natl Acad. Sci. USA 112, 5649–5654 (2015).
Linkevicius, M., Sandegren, L. & Andersson, D. I. Potential of tetracycline resistance proteins to evolve tigecycline resistance. Antimicrob. Agents Chemother. 60, 789–796 (2016).
Hentschke, M., Christner, M., Sobottka, I., Aepfelbacher, M. & Rohde, H. Combined ramR mutation and presence of a Tn1721-associated tet(A) variant in a clinical isolate of Salmonella enterica serovar Hadar resistant to tigecycline. Antimicrob. Agents Chemother. 54, 1319–1322 (2010).
He, T. et al. Occurrence and characterization of bla NDM-5-positive Klebsiella pneumoniae isolates from dairy cows in Jiangsu, China. J. Antimicrob. Chemother. 72, 90–94 (2017).
He, T. et al. Characterization of NDM-5-positive extensively resistant Escherichia coli isolates from dairy cows. Vet. Microbiol. 207, 153–158 (2017).
Wang, Y. et al. Comprehensive resistome analysis reveals the prevalence of NDM and MCR-1 in Chinese poultry production. Nat. Microbiol. 2, 16260 (2017).
Shen, Y. et al. Heterogeneous and flexible transmission of mcr-1 in hospital-associated Escherichia coli. mBio 9, e00943-18 (2018).
Li, R. et al. Efficient generation of complete sequences of MDR-encoding plasmids by rapid assembly of MinION barcoding sequencing data. Gigascience 7, 1–9 (2018).
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).