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Riboswitches as antibacterial drug targets

Nature Biotechnology volume 24, pages 1558–1564 (2006)Cite this article

Abstract

New validated cellular targets are needed to reinvigorate antibacterial drug discovery. This need could potentially be filled by riboswitches—messenger RNA (mRNA) structures that regulate gene expression in bacteria. Riboswitches are unique among RNAs that serve as drug targets in that they have evolved to form structured and highly selective receptors for small drug-like metabolites. In most cases, metabolite binding to the receptor represses the expression of the gene(s) encoded by the mRNA. If a new metabolite analog were designed that binds to the receptor, the gene(s) regulated by that riboswitch could be repressed, with a potentially lethal effect to the bacteria. Recent work suggests that certain antibacterial compounds discovered decades ago function at least in part by targeting riboswitches. Herein we will summarize the experiments validating riboswitches as drug targets, describe the existing technology for riboswitch drug discovery and discuss the challenges that may face riboswitch drug discoverers.

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Figure 1: TPP-binding riboswitches regulate gene expression.
Figure 2: The distribution of known riboswitch classes in selected bacterial pathogens.
Figure 3: Structural models of ligand-bound riboswitch receptors.
Figure 4: The chemical structures of riboswitch-binding natural metabolites (left) and antibacterial metabolite analogs (right).

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Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, 266 Whitney Avenue, New Haven, 06520, Connecticut, USA

    Kenneth F Blount & Ronald R Breaker

  2. Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, 06520, Connecticut, USA

    Ronald R Breaker

  3. Howard Hughes Medical Institute, Yale University, 266 Whitney Avenue, New Haven, 06520, Connecticut, USA

    Ronald R Breaker

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  1. Kenneth F Blount
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Correspondence to Kenneth F Blount or Ronald R Breaker.

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K.F.B. and R.R.B. are cofounders of BioRelix, a company that is pursuing intellectual property related to the use of riboswitches as drug targets.

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Blount, K., Breaker, R. Riboswitches as antibacterial drug targets. Nat Biotechnol 24, 1558–1564 (2006). https://doi.org/10.1038/nbt1268

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