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

Journal Article


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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 minimal 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 fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.

Publication Date


  • 2014

Citation


  • 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.

Scopus Eid


  • 2-s2.0-84897404977

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2564&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1546

Number Of Pages


  • 7

Start Page


  • 2799

End Page


  • 2806

Volume


  • 57

Issue


  • 6

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 minimal 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 fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.

Publication Date


  • 2014

Citation


  • 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.

Scopus Eid


  • 2-s2.0-84897404977

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2564&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1546

Number Of Pages


  • 7

Start Page


  • 2799

End Page


  • 2806

Volume


  • 57

Issue


  • 6