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Letter

Identification of Antibiotic Stress-Inducible Promoters: A Systematic Approach to Novel Pathway-Specific Reporter Assays for Antibacterial Drug Discovery

¹ Genedata AG, Postfach 254, CH-4016, Basel, Switzerland ² Bayer AG, Pharma Research (PH-R-EU-AI 1), D-42096 Wuppertal, Germany

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.

³ These authors contributed equally to this work.

⁴ Corresponding author.
E-MAIL Hans-Peter.Fischer{at}genedata.com; FAX 41-61-697 7244.

[Supplemental material is available online at www.genome.org.]

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