Abstract

A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug–microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.

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Acknowledgements

We thank P. Beltrao (EBI), K. C. Huang (Stanford) and F. Cabreiro (UCL) for feedback on the manuscript; F. Rippmann (Merck KGaA) for pointing to the delayed onset of antipsychotics; S. Wicha (University of Hamburg) for discussions on drug concentrations; J. Overington (Medicines Discovery Catapult) for help with drug plasma concentrations, and members of all four laboratories for fruitful discussions (in particular T. Hodges for suggestions on the manuscript and M. Driessen for experimental support). We thank the EMBL mechanical workshop for the custom-made incubator. We acknowledge funding from EMBL and the Microbios grant (ERC-AdG-669830). L.M. and M.P. were supported by the EMBL Interdisciplinary Postdoc (EIPOD) programme under Marie Sklodowska Curie Actions COFUND (grant 291772). A.Te. and A.R.B. were supported by a Sofja Kovaleskaja Award of the Alexander von Humboldt Foundation to A.Ty.

Author information

Author notes

    • Mihaela Pruteanu

    Present address: Institute for Biology, Humboldt University Berlin, 10115 Berlin, Germany.

    • Lisa Maier
    • , Mihaela Pruteanu
    •  & Michael Kuhn

    These authors contributed equally to this work.

Affiliations

  1. European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany

    • Lisa Maier
    • , Mihaela Pruteanu
    • , Anja Telzerow
    • , Exene Erin Anderson
    • , Ana Rita Brochado
    • , Keith Conrad Fernandez
    •  & Athanasios Typas
  2. European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany

    • Michael Kuhn
    • , Georg Zeller
    • , Kiran Raosaheb Patil
    • , Peer Bork
    •  & Athanasios Typas
  3. Graduate School of Biological Sciences, Nara Institute of Science and Technology, 630-0101 Ikoma, Japan

    • Hitomi Dose
    •  & Hirotada Mori
  4. Max-Delbrück-Centre for Molecular Medicine, 13125 Berlin, Germany

    • Peer Bork
  5. Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany

    • Peer Bork
  6. Department of Bioinformatics, Biocenter, University of Würzburg, 97024 Würzburg, Germany.

    • Peer Bork

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Contributions

The study was conceived by K.R.P., P.B. and A.Ty., designed by L.M., M.P., G.Z., A.R.B. and A.Ty., and supervised by K.R.P., P.B. and A.Ty. In vitro screening was established by M.P. and performed by L.M., M.P., A.Te. and K.C.F. Follow-up and validation experiments were conducted by L.M., M.P. and E.E.A. H.D. and H.M. constructed and provided the Transbac library. Data preprocessing was performed by M.K. and G.Z.; statistical analyses by M.K.; data curation by L.M., M.K. and E.E.A.; data interpretation by L.M., M.P., M.K., G.Z., K.R.P., P.B. and A.Ty. L.M., M.K., G.Z., K.R.P., P.B. and A.Ty. wrote the manuscript with input from M.P. and A.R.B.; L.M., M.K. and G.Z. designed figures with input from K.R.P., P.B. and A.Ty. All authors approved the final version for publication.

Competing interests

EMBL has filed two patent applications on repurposing compounds identified in this study for the treatment of infections and for modulating the composition of the gut microbiome, and on the use of the in vitro model of the human gut microbiome to study the impact of xenobiotics (Tentative European patent application numbers EP 18156520 and EP 18155278, respectively). Authors L.M., M.P., M.K., G.Z., K.R.P., P.B. and A.T. are listed as inventors.

Corresponding authors

Correspondence to Georg Zeller or Kiran Raosaheb Patil or Peer Bork or Athanasios Typas.

Reviewer Information Nature thanks K. Lewis, H. B. Nielsen, G. Wright and R. Xavier for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains a Supplementary Discussion.

Excel files

  1. 1.

    Supplementary Table 1

    This file shows the compounds used in this study. Sheet 1 shows the compounds of the Prestwick Chemical Library, their assignment to therapeutic classes according to the ATC classification system, chemical and physical properties, single doses (which are half of the daily doses), plasma concentrations, estimated small intestine concentrations, route of excretion, estimated colon concentrations and conversion of the molar concentration of the screen (20 μM) into μg/ml. Sheet 2 shows the chemicals used in this study.

  2. 2.

    Supplementary Table 2

    This file contains the strains used in this study, their medium requirements and starting ODs for drug screening in 96- or 384-format.

  3. 3.

    Supplementary Table 3

    This file contains drugs with anticommensal activity in our screen. Sheet 1 shows the adjusted p-values for the impact of 1197 drugs on anaerobic growth of 40 human gut bacteria (see Methods). Sheet 2 shows the literature evidence and lowest measured MICs for antibacterial activity of the top 40 human-targeted drugs that affect more than 10 strains in our screen.

  4. 4.

    Supplementary Table 4

    This file contains IC25 determination which shows 25 selected drugs in a subset of up to 27 strains.

  5. 5.

    Supplementary Table 5

    This file contains the antibiotic-related side effects in human-targeted drugs (see Methods).

  6. 6.

    Supplementary Table 6

    This file contains the screen results of additionally screened strains (Figure 4), which shows the E. coli ΔtolC, its parental background (BW25113) and of B. fragilis HM-20 (NT5057) and B. uniformis HM-715 (NT5065).

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DOI

https://doi.org/10.1038/nature25979

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