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Functional classification of drugs by properties of their pairwise interactions

Nature Genetics volume 38, pages 489–494 (2006)Cite this article

Abstract

Multidrug treatments are increasingly important in medicine and for probing biological systems1,2,3,4,5,6. Although many studies have focused on interactions between specific drugs, little is known about the system properties of a full drug interaction network6. Like their genetic counterparts, two drugs may have no interaction, or they may interact synergistically or antagonistically to increase or suppress their individual effects. Here we use a sensitive bioluminescence technique7,8 to provide quantitative measurements of pairwise interactions among 21 antibiotics that affect growth rate in Escherichia coli. We find that the drug interaction network possesses a special property: it can be separated into classes of drugs such that any two classes interact either purely synergistically or purely antagonistically. These classes correspond directly to the cellular functions affected by the drugs. This network approach provides a new conceptual framework for understanding the functional mechanisms of drugs and their cellular targets and can be applied in systems intractable to mutant screening, biochemistry or microscopy.

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Figure 1: Clustering of individual drugs into functional classes solely on the basis of properties of their mutual interaction network.
Figure 2: Experimental classification of drug interactions into four types using bioluminescence measurements of bacterial growth in the presence of sublethal concentrations of antibiotics.
Figure 3: Systematic measurements of pairwise interactions between antibiotics.
Figure 4: Unsupervised classification of the antibiotic network into monochromatically interacting classes of drugs with similar mechanisms of action.

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Acknowledgements

We thank N. Barkai, J. Clardy, A. De Luna, M. Elowitz, L. Garwin, M. Hegreness, H. Hofmann, D. Kahne, G. Lahav, M. Laub, T. Mitchison, A. Murray, E. O'Shea, S. Renn, V. Savage, D. Segrè, N. Shoresh and C. Walsh for helpful suggestions and for comments on the manuscript. We acknowledge support from the Bauer Center for Genomics Research.

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Authors and Affiliations

  1. Bauer Center for Genomics Research, Harvard University, 7 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Pamela Yeh, Ariane I Tschumi & Roy Kishony

  2. Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Roy Kishony

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  1. Pamela Yeh
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  2. Ariane I Tschumi
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Correspondence to Roy Kishony.

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Supplementary information

Supplementary Fig. 1

Reproducibility of growth rate measurements using the bioluminescence technique. (PDF 40 kb)

Supplementary Fig. 2

Single-drug dose-reponse measurements. (PDF 52 kb)

Supplementary Fig. 3

Examining dose dependence drug interactions. (PDF 57 kb)

Supplementary Fig. 4

Monochromaticity exhibited by the drug network is a special property not exhibited in random networks. (PDF 21 kb)

Supplementary Note (PDF 64 kb)

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Yeh, P., Tschumi, A. & Kishony, R. Functional classification of drugs by properties of their pairwise interactions. Nat Genet 38, 489–494 (2006). https://doi.org/10.1038/ng1755

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