Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence

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• 作者：Nicolas Desroy ; Alexis Denis ; Chrystelle Oliveira ; Dmytro Atamanyuk ; Sophia Briet ; Fabien Faivre ; G茅raldine LeFralliec ; Yannick Bonvin ; Mayalen Oxoby ; Sonia Escaich ; St茅phanie Floquet ; Elodie Drocourt ; Vanida Vongsouthi ; Lionel Durant ; Fran莽ois Moreau ; Theodore B. Verhey ; Ting-Wai Lee ; Murray S. Junop ; Vincent Gerusz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1418-1430
• 全文大小：572K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 渭g/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.