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

20 Citations (Scopus)

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
Externally publishedYes

Fingerprint

DNA Replication
DNA Polymerase III
Escherichia coli
Proteins
X Ray Crystallography
Prodrugs
Gram-Positive Bacteria
Microbial Sensitivity Tests
Esters
Lead
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Liu, M., Harry, E. 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

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. / Yin, Zhou; Whittell, Louise R.; Wang, Yao; Jergic, Slobodan; Liu, Michael; Harry, Elizabeth J.; Dixon, Nicholas E.; Beck, Jennifer L.; Kelso, Michael J.; Oakley, Aaron J.

In: Journal of Medicinal Chemistry, Vol. 57, No. 6, 27.03.2014, p. 2799-2806.

Research output: Contribution to journalArticle

Yin, Z, Whittell, LR, Wang, Y, Jergic, S, Liu, M, Harry, EJ, Dixon, NE, Beck, JL, Kelso, MJ & Oakley, AJ 2014, 'Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach', Journal of Medicinal Chemistry, vol. 57, no. 6, pp. 2799-2806. https://doi.org/10.1021/jm500122r
Yin, Zhou ; Whittell, Louise R. ; Wang, Yao ; Jergic, Slobodan ; Liu, Michael ; Harry, Elizabeth J. ; Dixon, Nicholas E. ; Beck, Jennifer L. ; Kelso, Michael J. ; Oakley, Aaron J. / Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 6. pp. 2799-2806.
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