Prediction of mechanisms of action of antibacterial compounds by gene expression profiling.
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.
GPC Biotech AG, Microbiology, Munich, Germany. bernd.hutter@gpc-biotech.com
Bernd
B
Hutter
Christoph
C
Schaab
Sebastian
S
Albrecht
Matthias
M
Borgmann
Nina A
NA
Brunner
Christoph
C
Freiberg
Karl
K
Ziegelbauer
Charles O
CO
Rock
Igor
I
Ivanov
Hannes
H
Loferer
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D002473:Cell Wall / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics; D030541:Databases, Genetic; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006582:Hexachlorophene / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011237:Predictive Value of Tests; D012329:RNA, Bacterial / Q000032:analysis / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D004269:DNA, Bacterial; D012329:RNA, Bacterial; D009243:NAD; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D006582:Hexachlorophene