Antibiotic resistance is ancient

Abstract

The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes1,2. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics3. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.

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Figure 1: Stratigraphic profile and location of Bear Creek site.
Figure 2: Genetic diversity of ancient antibiotic resistance elements.
Figure 3: Ancient vancomycin resistance elements.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

The metagenomic sequences determined from permafrost are deposited in GenBank under accession numbers JN316287–JN366376.

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Acknowledgements

We thank A. Guarné for assistance in X-ray data collection. This work was supported by Canada Research Chairs to D.F., H.N.P. and G.D.W., a Canadian Institutes of Health Research operating grant to G.D.W. (MOP-79488) and a scholarship to V.M.D., and by grants from the Natural Sciences and Engineering Research Council of Canada to D.F. and H.N.P. and scholarship to C.E.K.

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Contributions

D.F., G.Z. and F.C. collected permafrost cores and performed geochemical analyses followed by subsampling by C.S., V.M.D. and C.E.K. C.E.K performed ancient DNA laboratory work and 454 sequencing. V.M.D. designed primers for resistance genes, 16S and gfp. V.M.D. and C.E.K. designed and optimized the qPCR assays, and cloned and sequenced the resistance gene products. R.D. independently confirmed the results in France. L.K. purified and characterized VanA, and M.M. crystallized VanA and determined the three-dimensional structure. W.S., G.B.G., C.E.K. and H.N.P. processed and analysed the floral/faunal data; V.M.D. and G.B.G. performed phylogenetic and bioinformatic analyses of the resistance gene sequences. H.N.P. and G.D.W. conceived the project, and V.M.D., C.E.K., D.F., H.N.P. and G.D.W. wrote the manuscript. All authors edited the final draft.

Corresponding authors

Correspondence to Hendrik N. Poinar or Gerard D. Wright.

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The authors declare no competing financial interests.

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The file contains Supplementary Text, Supplementary Figures 1-14 with legends and Supplementary Tables 1-12. (PDF 3142 kb)

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D’Costa, V., King, C., Kalan, L. et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011). https://doi.org/10.1038/nature10388

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