Discovery of Novel Bacterial RNA Polymerase Inhibitors: Pharmacophore-Based Virtual Screening and Hit Optimization

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• 作者：Stefan Hinsberger ; Kristina H眉secken ; Matthias Groh ; Matthias Negri ; J枚rg Haupenthal ; Rolf W. Hartmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8332-8338
• 全文大小：289K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein鈥損rotein interaction (PPI) between 蟽⁷⁰ and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.