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Journal of Biomolecular Screening, Vol. 12, No. 8, 1102-1108 (2007)
DOI: 10.1177/1087057107308161
© 2007 Society for Biomolecular Sciences

Differential Assay for High-Throughput Screening of Antibacterial Compounds

Shaun P. Falk

Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Andrew T. Ulijasz

Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, Department of Genetics, University of Wisconsin, Madison

Bernard Weisblum

Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, weisblum{at}wisc.edu

The previously described Bacillus subtilis reporter strain BAU-102 is capable of detecting cell wall synthesis inhibitors that act at all stages of the cell wall synthesis pathway. In addition, this strain is capable of detecting compounds with hydrophobic/ surfactant activity and alternative mechanisms of cell wall disruption. BAU-102 sequesters preformed β-gal in the periplasm, suggesting leakage of β-gal as the means by which this assay detects compound activities. A model is proposed according to which β-gal release by BAU-102 reflects activation of pathways leading to autolysis. The authors also report a simplified high-throughput assay using BAU-102 combined with the fluorogenic substrate N-methylumbelliferyl-β-D-galactoside as a single reagent. Cell wall inhibitors release β-gal consistently only after 60 min of incubation, whereas compounds with surfactant activity show an almost immediate release. A high-throughput screen of a 480-compound library of known bioactives yielded 8 compounds that cause β-gal release. These results validate the BAU-102 assay as an effective tool in antimicrobial drug discovery. (Journal of Biomolecular Screening 2007:1102-1108)

Key Words: assay development • screening • β-galactosidase reporter • peptidoglycan synthesis • hydrophobicity • surfactant


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