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Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy

Nature Chemical Biology volume 7, pages 348–350 (2011)Cite this article

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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.

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

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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.

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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

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  1. Linda Ejim
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  2. Maya A Farha
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  7. Eric D Brown
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  8. Gerard D Wright
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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.

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The authors declare no competing financial interests.

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

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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

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