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Antibiotic interactions that select against resistance

Nature volume 446, pages 668–671 (2007)Cite this article

Abstract

Multidrug combinations are increasingly important in combating the spread of antibiotic-resistance in bacterial pathogens1,2,3. On a broader scale, such combinations are also important in understanding microbial ecology and evolution4,5. Although the effects of multidrug combinations on bacterial growth have been studied extensively, relatively little is known about their impact on the differential selection between sensitive and resistant bacterial populations1,6,7. Normally, the presence of a drug confers an advantage on its resistant mutants in competition with the sensitive wild-type population1. Here we show, by using a direct competition assay between doxycycline-resistant and doxycycline-sensitive Escherichia coli, that this differential selection can be inverted in a hyper-antagonistic class of drug combinations. Used in such a combination, a drug can render the combined treatment selective against the drug’s own resistance allele. Further, this inversion of selection seems largely insensitive to the underlying resistance mechanism and occurs, at sublethal concentrations, while maintaining inhibition of the wild type. These seemingly paradoxical results can be rationalized in terms of a simple geometric argument. Our findings demonstrate a previously unappreciated feature of the fitness landscape for the evolution of resistance and point to a trade-off between the effect of drug interactions on absolute potency and the relative competitive selection that they impose on emerging resistant populations.

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Figure 1: Schematic representation of synergistic, additive, antagonistic and suppressive drug pairs.
Figure 2: Rescaling of effective drug concentrations by resistance generates a region exclusive to growth of sensitive bacteria in a suppressive drug combination.
Figure 3: Competitive selection against resistance in a suppressive drug combination.

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Acknowledgements

We thank U. Alon, N. Q. Balaban, B. Chait, J. Davies, M. Elowitz, Y. Fink, L. Garwin, D. Hartl, M. Hegreness, D. Kahne, M. Kirschner, S. Leibler, R. Lenski, R. Milo, T. Mitchison, R. Moellering, A. Murray, D. Segre', N. Shoresh, S. Walker, C. Walsh, R. Ward and P. Yeh for comments and valuable discussions; and G. Jacoby, N. Shoemaker and G. Wright for their gifts of plasmids. This work was supported partly by a grant from the Human Frontiers Science Program.

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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA,

    Remy Chait, Allison Craney & Roy Kishony

  2. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA,

    Roy Kishony

Authors
  1. Remy Chait
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Correspondence to Roy Kishony.

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Supplementary information

Supplementary Information

This file includes Supplementary Figures S1-S7 with Legends, Supplementary Tables S1-S3 and additional references. Supplementary Table S1 shows doxycycline-erythromycin competition data, Supplementary Table S2 shows doxycycline-ciprofloxacin competition data, Supplementary Table S3 shows strains and plasmids. (PDF 4677 kb)

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Chait, R., Craney, A. & Kishony, R. Antibiotic interactions that select against resistance. Nature 446, 668–671 (2007). https://doi.org/10.1038/nature05685

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