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Bugs, drugs and chemical genomics

Abstract

The serendipitous discovery of penicillin inspired intensive research into how small molecules affect basic cellular processes and their potential to treat disease. Biochemical and genetic approaches have been fundamental for clarifying small-molecule modes of action. Genomic technologies have permitted the use of chemical-genetic strategies that comprehensively study compound-target relationships in the context of a living cell, providing a systems biology view of both the cellular targets and the interdependent networks that respond to chemical stress. These studies highlight the fact that in vitro determinations of mechanism rarely translate into a complete understanding of drug behavior in the cell. Here, we review key discoveries that gave rise to the field of chemical genetics, with particular attention to chemical-genetic strategies developed for bakers' yeast, their extension to clinically relevant microbial pathogens, and the potential of these approaches to affect antimicrobial drug discovery.

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Figure 1: Yeast fitness profiling of pooled deletion strains.
Figure 2: Yeast chemogenomic platform that interrogates three different yeast pools with a single TAG4 array.
Figure 3: C. albicans fitness test assay.
Figure 4: Chemical structures of recently discovered antimicrobial compounds identified through genome-wide chemical-genetic methodologies.
Figure 5: Methicillin-resistant S. aureus (MRSA) chemical-genetic screening by transposon insertional inactivation and modulation of gene expression.
Figure 6: Chemical-genetic interaction map of MRSA strain USA300 with cell-wall antibiotics.
Figure 7: Construction of tagged transposon mutants in C. albicans.

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Acknowledgements

We are grateful to the anonymous reviewers for their suggestions to improving the review article. We also thank I. Wallace for assistance in preparing the figures.

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Correspondence to Terry Roemer or Corey Nislow.

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T.R. is an employee of Merck and may own stock and/or stock options in the company.

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Roemer, T., Davies, J., Giaever, G. et al. Bugs, drugs and chemical genomics. Nat Chem Biol 8, 46–56 (2012). https://doi.org/10.1038/nchembio.744

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