Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

Zhou Yin, Louise R. Whittell, Yao Wang, Slobodan Jergic, Michael Liu, Elizabeth J. Harry, Nicholas E. Dixon, Jennifer L. Beck, Michael J. Kelso, Aaron J. Oakley

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.

Original languageEnglish (US)
Pages (from-to)2799-2806
Number of pages8
JournalJournal of medicinal chemistry
Volume57
Issue number6
DOIs
StatePublished - Mar 27 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Liu, M., Harry, E. J., Dixon, N. E., Beck, J. L., Kelso, M. J., & Oakley, A. J. (2014). Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. Journal of medicinal chemistry, 57(6), 2799-2806. https://doi.org/10.1021/jm500122r