Skip to main content

Advertisement

SpringerLink
Log in

Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy

  • Brief Communication
  • Published:

From Nature Chemical Biology

View current issue Submit your manuscript

Abstract

Combinations of antibiotics are commonly used in medicine to broaden antimicrobial spectrum and generate synergistic effects. Alternatively, combination of nonantibiotic drugs with antibiotics offers an opportunity to sample a previously untapped expanse of bioactive chemical space. We screened a collection of drugs to identify compounds that augment the activity of the antibiotic minocycline. Unexpected synergistic drug combinations exhibited in vitro and in vivo activity against bacterial pathogens, including multidrug–resistant isolates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Nonantibiotic molecules synergize with the antibiotic minocycline.
Figure 2: Mechanism of tetracycline-loperamide synergy.

Similar content being viewed by others

References

  1. Boucher, H.W. et al. Clin. Infect. Dis. 48, 1–12 (2009).

    Article  Google Scholar 

  2. Parsons, A.B. et al. Nat. Biotechnol. 22, 62–69 (2004).

    Article  CAS  Google Scholar 

  3. Costanzo, M. et al. Science 327, 425–431 (2010).

    Article  CAS  Google Scholar 

  4. Sharom, J.R., Bellows, D.S. & Tyers, M. Curr. Opin. Chem. Biol. 8, 81–90 (2004).

    Article  CAS  Google Scholar 

  5. Lehár, J. et al. Mol. Syst. Biol. 3, 80 (2007).

    Article  Google Scholar 

  6. Walsh, C. Nature 406, 775–781 (2000).

    Article  CAS  Google Scholar 

  7. Borisy, A.A. et al. Proc. Natl. Acad. Sci. USA 100, 7977–7982 (2003).

    Article  CAS  Google Scholar 

  8. Chong, C.R. & Sullivan, D.J. Jr. Nature 448, 645–646 (2007).

    Article  CAS  Google Scholar 

  9. Stolk, P., Willemen, M.J. & Leufkens, H.G. Bull. World Health Organ. 84, 745–751 (2006).

    Article  Google Scholar 

  10. Kristiansen, J.E. et al. J. Antimicrob. Chemother. 59, 1271–1279 (2007).

    Article  CAS  Google Scholar 

  11. Lehtinen, J. & Lilius, E.M. Int. J. Antimicrob. Agents 30, 44–51 (2007).

    Article  CAS  Google Scholar 

  12. Mazumdar, K., Dastidar, S.G., Park, J.H. & Dutta, N.K. Eur. J. Clin. Microbiol. Infect. Dis. 28, 881–891 (2009).

    Article  CAS  Google Scholar 

  13. Pillai, S.K., Moellering, R.C. & Eliopoulos, G.M. Antimicrobial combinations. in Antibiotics in Laboratory Medicine (Lorian, V., ed.) 365–440 (Williams and Wilkins, Baltimore, 2005).

  14. Odds, F.C. J. Antimicrob. Chemother. 52, 1 (2003).

    Article  CAS  Google Scholar 

  15. Christianson, S., Golding, G.R., Campbell, J. & Mulvey, M.R. J. Clin. Microbiol. 45, 1904–1911 (2007).

    Article  CAS  Google Scholar 

  16. Kruszewska, H., Zareba, T. & Tyski, S. Acta Pol. Pharm. 61 Suppl: 18–21 (2004).

    CAS  PubMed  Google Scholar 

  17. Barthel, M. et al. Infect. Immun. 71, 2839–2858 (2003).

    Article  CAS  Google Scholar 

  18. Hurwitz, A., Sztern, M.I., Looney, G.A. & Ben-Zvi, Z. Life Sci. 54, 1687–1698 (1994).

    Article  CAS  Google Scholar 

  19. Liu, A. et al. Antimicrob. Agents Chemother. 54, 1393–1403 (2010).

    Article  CAS  Google Scholar 

  20. Taber, H.W., Mueller, J.P., Miller, P.F. & Arrow, A.S. Microbiol. Rev. 51, 439–457 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cascales, E., Gavioli, M., Sturgis, J.N. & Lloubes, R. Mol. Microbiol. 38, 904–915 (2000).

    Article  CAS  Google Scholar 

  22. Yamaguchi, A., Ohmori, H., Kaneko-Ohdera, M., Nomura, T. & Sawai, T. Antimicrob. Agents Chemother. 35, 53–56 (1991).

    Article  CAS  Google Scholar 

  23. Paul, K., Erhardt, M., Hirano, T., Blair, D.F. & Hughes, K.T. Nature 451, 489–492 (2008).

    Article  CAS  Google Scholar 

  24. Chopra, I. & Hacker, K. FEMS Microbiol. Lett. 51, 21–24 (1989).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the staff of the McMaster High Throughput Screening Laboratory for technical assistance. The work was supported by Canada Research Chairs to E.D.B., M.T., G.D.W., the Canadian Cystic Fibrosis Foundation, Canadian Institutes of Health Research operating grants to E.D.B. (MOP-81330), G.D.W. (XNE-8705, FRN-79488) and the European Research Council to M.T.

Author information

Authors and Affiliations

  1. M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada

    Linda Ejim, Maya A Farha, Shannon B Falconer, Brian K Coombes, Eric D Brown & Gerard D Wright

  2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Linda Ejim, Maya A Farha, Shannon B Falconer, Brian K Coombes, Eric D Brown & Gerard D Wright

  3. Wellcome Trust Centre for Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, UK

    Jan Wildenhain & Mike Tyers

Authors
  1. Linda Ejim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maya A Farha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shannon B Falconer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Wildenhain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian K Coombes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mike Tyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric D Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gerard D Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.E. established screening conditions, ran the screens and determined synergy profiles for the compounds. J.W. prepared the PAD library, and M.A.F., L.E. and S.B.F. performed the mode-of-action studies on the loperamide-tetracycline pair. B.K.C. performed the mouse infectious studies. G.D.W., E.D.B., M.T. and B.K.C. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Eric D Brown or Gerard D Wright.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Results, Supplementary Tables 1–10, Supplementary Figures 1–6 and Supplementary Scheme 1 (PDF 4634 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ejim, L., Farha, M., Falconer, S. et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 7, 348–350 (2011). https://doi.org/10.1038/nchembio.559

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.559

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation