4n95

Publication Abstract from PubMed

The bacterial sliding clamp (SC), also known as the DNA polymerase III beta 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 mug/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.

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach.,Yin Z, Whittell LR, Wang Y, Jergic S, Liu M, Harry EJ, Dixon NE, Beck JL, Kelso MJ, Oakley AJ J Med Chem. 2014 Mar 27;57(6):2799-806. doi: 10.1021/jm500122r. Epub 2014 Mar 18. PMID:24592885^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.