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Originally published In Press as doi:10.1074/mcp.M600127-MCP200 on August 29, 2006.
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Molecular & Cellular Proteomics 5:2326-2335, 2006.
© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Discovering Antibiotic Efficacy Biomarkers

TOWARD MECHANISM-SPECIFIC HIGH CONTENT COMPOUND SCREENING*,S

Christoph Freiberg{ddagger},§,**, Nina Brunner{ddagger},§,{ddagger}{ddagger}, Ludwig Macko and Hans Peter Fischer,||

From {ddagger} Pharma Global Drug Discovery, European Research Center, Bayer HealthCare AG, D-42096 Wuppertal, Germany and Genedata AG, Postfach 254, CH-4016 Basel, Switzerland

As current antibiotic therapy is increasingly challenged by emerging drug-resistant bacteria, new technologies are required to identify and develop novel classes of antibiotics. A major bottleneck in today’s discovery efforts, however, is a lack of an efficient and standardized method for assaying the efficacy of a drug candidate. We propose a new high content screening approach for identifying efficacious molecules suitable for development of antibiotics. Key to our approach is a new microarray-based efficacy biomarker discovery strategy. We first produced a large dataset of transcriptional responses of Bacillus subtilis to numerous structurally diverse antibacterial drugs. Second we evaluated different protocols to optimize drug concentration and exposure time selection for profiling compounds of unknown mechanism. Finally we identified a surprisingly low number of gene transcripts (~130) that were sufficient for identifying the mechanism of novel substances with reasonable accuracy (~90%). We show that the statistics-based approach reveals a physiologically meaningful set of biomarkers that can be related to major bacterial defense mechanisms against antibiotics. We provide statistical evidence that a parallel measurement of the expression of the biomarkers guarantees optimal performance when using expression systems for screening libraries of novel substances. The general approach is also applicable to drug discovery for medical indications other than infectious diseases.

|| To whom correspondence should be addressed. Tel.: 41-61-6976767; Fax: 41-61-6977244; E-mail: Hans-Peter.Fischer{at}genedata.com


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Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.