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Journal of Biomolecular Screening
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A Strategy for Discovery of Novel Broad-Spectrum Antibacterials Using a High-Throughput Streptococcus pneumoniae Transcription/Translation Screen

Steven D. Pratt

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL steve.d.pratt{at}abbot.com

Caroline A. David

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Candace Black-Schaefer

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Peter J. Dandliker

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Xiaoling Xuei

Indiana University School of Medicine, Indianapolis, IN

Usha Warrior

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

David J. Burns

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Ping Zhong

Givaudan Flavor Corp., Cincinnati, OH

Zhensheng Cao

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Anne Y. C. Saiki

Amgen, Inc., Thousand Oaks, CA

Claude G. Lerner

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Linda E. Chovan

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Niru B. Soni

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Angela M. Nilius

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Frank L. Wagenaar

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Philip J. Merta

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Linda M. Traphagen

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

Bruce A. Beutel

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL

The authors report the development of a high-throughput screen for inhibitors of Streptococcus pneumoniae transcription and translation (TT) using a luciferase reporter, and the secondary assays used to determine the biochemical spectrum of activity and bacterial specificity. More than 220,000 compounds were screened in mixtures of 10 compounds per well, with 10,000 picks selected for further study. False-positive hits from inhibition of luciferase activity were an extremely common artifact. After filtering luciferase inhibitors and several known classes of antibiotics, approximately 50 hits remained. These compounds were examined for their ability to inhibit Escherichia coli TT, uncoupled S. pneumoniae translation or transcription, rabbit reticulocyte translation, and in vitro toxicity in human and bacterial cells. One of these compounds had the desired profile of broad-spectrum biochemical activity in bacteria and selectivity versus mammalian biochemical and whole-cell assays. (Journal of Biomolecular Screening 2004:3-11)

Key Words: translation • transcription • Streptococcus • screen • antibacterial

Journal of Biomolecular Screening, Vol. 9, No. 1, 3-11 (2004)
DOI: 10.1177/1087057103260876
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