Identification of Antibiotic Stress-Inducible Promoters: A Systematic Approach to Novel Pathway-Specific Reporter Assays for Antibacterial Drug Discovery
Abstract
As present antibiotics therapy becomes increasingly ineffectual, new technologies are required to identify and develop novel classes of antibacterial agents. An attractive alternative to the classical target-based approach is the use of promoter-inducible reporter assays for high-throughput screening. The wide usage of these assays is, however, limited by the small number of specifically responding promoters that are known at present. This work describes a novel approach for identifying genetic regulators that are suitable for the design of pathway-specific assays. The basis for the proposed strategy is a large set of antibiotics-triggered expression profiles (“Reference Compendium”). Pattern recognition algorithms applied to the expression data pinpoint the relevant transcription-factor-binding sites in whole-genome sequences. Using this technique, we constructed a fatty-acid-pathway-specific reporter assay that is based on a novel stress-inducible promoter. In a proof-of-principle experiment, this assay was shown to enable screening for new small-molecule inhibitors of bacterial growth.
Footnotes
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[Supplemental material is available online at www.genome.org.]
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Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.1275704.
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↵3 These authors contributed equally to this work.
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↵4 Corresponding author. E-MAIL Hans-Peter.Fischer{at}genedata.com; FAX 41-61-697 7244.
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- Accepted November 4, 2003.
- Received February 17, 2003.
- Cold Spring Harbor Laboratory Press
