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Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy


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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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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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.

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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).

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