A strategy for discovery of novel broad-spectrum antibacterials using a high-throughput Streptococcus pneumoniae transcription/translation screen

Steven D. Pratt, Caroline A. David, Candace Black-Schaefer, Peter J. Dandliker, Xiaoling Xuei, Usha Warrior, David J. Burns, Ping Zhong, Zhensheng Cao, Anne Y.C. Saiki, Claude G. Lerner, Linda E. Chovan, Niru B. Soni, Angela M. Nilius, Frank L. Wagenaar, Philip J. Merta, Linda M. Traphagen, Bruce A. Beutel

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3-11
Number of pages9
JournalJournal of Biomolecular Screening
Volume9
Issue number1
DOIs
StatePublished - Feb 1 2004

Keywords

  • Antibacterial
  • Screen
  • Streptococcus
  • Transcription
  • Translation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Clinical Biochemistry
  • Biotechnology
  • Biochemistry
  • Molecular Biology

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  • Cite this

    Pratt, S. D., David, C. A., Black-Schaefer, C., Dandliker, P. J., Xuei, X., Warrior, U., Burns, D. J., Zhong, P., Cao, Z., Saiki, A. Y. C., Lerner, C. G., Chovan, L. E., Soni, N. B., Nilius, A. M., Wagenaar, F. L., Merta, P. J., Traphagen, L. M., & Beutel, B. A. (2004). A strategy for discovery of novel broad-spectrum antibacterials using a high-throughput Streptococcus pneumoniae transcription/translation screen. Journal of Biomolecular Screening, 9(1), 3-11. https://doi.org/10.1177/1087057103260876