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In our quest for new antibiotics able to address the growing threat of multi-drug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for ImidazoPYrazinones as part of the IMI ENABLE organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy and a good developability profile although later profiling revealed a genotoxicity risk. Resistance studies revealed partial cross-resistance with fluoro-quinolones (FQs) suggesting that IPYs bind to the same region of bacterial topoisomerases as FQs and interact with at least some of the keys residues involved in FQ binding.
This article was published in the following journal.
Name: Journal of medicinal chemistry
The inhibition of pathogenic bacteria at the replication stage is important to halt their further reproduction and spread. The replication enzymes include the DNA gyrase and topoisomerase IV that are ...
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A bacterial DNA topoisomerase II that catalyzes ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. Topoisomerase IV binds to DNA as a heterotetramer consisting 2 parC and 2 parE subunits. Topoisomerase IV is a decatenating enzyme that resolves interlinked daughter chromosomes following DNA replication.
Compounds that inhibit the activity of DNA TOPOISOMERASE I.
Compounds that inhibit the activity of DNA TOPOISOMERASE II.
Compounds that inhibit the activity of DNA TOPOISOMERASES.
Enzymes that regulate the topology of DNA by actions such as breaking, relaxing, passing, and rejoining strands of DNA in cells. These enzymes are important components of the DNA replication system. They are classified by their substrate specificities. DNA TOPOISOMERASE I enzymes act on a single strand of DNA. DNA TOPOISOMERASE II enzymes act on double strands of DNA.
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