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Prediction of Mechanisms of Action of Antibacterial Compounds by Gene Expression Profiling

Bernd Hutter,^1* Christoph Schaab,¹ Sebastian Albrecht,^1, Matthias Borgmann,¹ Nina A. Brunner,² Christoph Freiberg,² Karl Ziegelbauer,² Charles O. Rock,³ Igor Ivanov,¹ and Hannes Loferer^1*

GPC Biotech AG, Munich,¹ Bayer AG, Wuppertal, Germany,² Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105³

Received 30 October 2003/ Returned for modification 24 January 2004/ Accepted 3 April 2004

We have generated a database of expression profiles carrying the transcriptional responses of the model organism Bacillus subtilis following treatment with 37 well-characterized antibacterial compounds of different classes. The database was used to build a predictor for the assignment of the mechanisms of action (MoAs) of antibacterial compounds by the use of support vector machines. This predictor was able to correctly classify the MoA class for most compounds tested. Furthermore, we provide evidence that the in vivo MoA of hexachlorophene does not match the MoA predicted from in vitro data, a situation frequently faced in drug discovery. A database of this kind may facilitate the prioritization of novel antibacterial entities in drug discovery programs. Potential applications and limitations are discussed.

Present address: Leogic GmbH, Munich, Germany.

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