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Systems-level antimicrobial drug and drug synergy discovery

Nature Chemical Biology volume 9, pages 222–231 (2013)Cite this article

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Abstract

Here, we review the 'target-centric' genomic strategy to antimicrobial discovery and share our perspective on identification, validation and prioritization of potential antimicrobial drug targets in the context of emerging chemical biology, genomics and phenotypic screening strategies. We propose that coupling the dual processes of antimicrobial small-molecule screening and target identification in a whole-cell context is essential to empirically annotate 'druggable' targets and advance early stage antimicrobial discovery. We also advocate a systems-level approach to annotating synthetic-lethal genetic interactions comprehensively within yeast and bacteria models. The resulting genetic interaction networks provide a landscape to rationally predict and exploit drug synergy between cognate inhibitors. We posit that synergistic combination agents provide an important and largely unexploited strategy to 'repurpose' existing chemical space and simultaneously address issues of potency, spectrum, toxicity and drug resistance in early stages of antimicrobial drug discovery.

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Figure 1
Figure 2: Identifying bioactive antimicrobial compounds and linking them to their target with forward and reverse chemical-genetic approaches.
Figure 3: Interpreting chemical-genetic and genetic interaction profiles.
Figure 4: Genetic interactions are predictive of chemical-genetic and chemical-synergy interactions.

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Acknowledgements

We thank M. Costanzo, J. Piotrowski and S. Li for contributions to this manuscript. This work was supported by a grant from the Canadian Institutes of Health Research (MOP-57830) to C.B.

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Authors and Affiliations

  1. Infectious Disease Research, Merck Research Laboratories, Kenilworth, New Jersey, USA

    Terry Roemer

  2. Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

    Charles Boone

  3. Department of Molecular Genetics, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada

    Charles Boone

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Correspondence to Terry Roemer or Charles Boone.

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Competing interests

Terry Roemer is an employee of Merck, as stated in the affiliations, and potentially owns stock and/or holds stock in the company.

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Roemer, T., Boone, C. Systems-level antimicrobial drug and drug synergy discovery. Nat Chem Biol 9, 222–231 (2013). https://doi.org/10.1038/nchembio.1205

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