Hybrid Antibacterials. DNA Polymerase−Topoisomerase Inhibitors
Year: 2006
Type: article
Abstract: Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm0510023
Authors: Chengxin Zhi, Zheng-yu Long, Andrzej Manikowski, Jeanne Comstock, Wei-Chu Xu, Neal C. Brown, Paul M. Tarantino,, Karsten A. Holm, Edward J. Dix, George E. Wright, Marjorie H. Barnes, Michelle M. Butler, Kimberly A. Foster, William A. LaMarr, Benoit Bachand, Richard Bethell, Caroline Cadilhac, Sylvie Charron, Serge Lamothe, Irina Motorina, Richard Storer
Institutions: Glsynthesis, Microbiotix (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1976224957