DNA Gyrase Interaction with Coumarin-Based Inhibitors: The Role of the Hydroxybenzoate Isopentenyl Moiety and the 5'-Methyl Group of the Noviose

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• 作者：Daniel Lafitte ; Valé ; rie Lamour ; Philippe O. Tsvetkov ; Alexander A. Makarov ; Michel Klich ; Pierre Deprez ; Dino Moras ; Claudette Briand ; and Robert Gilli
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：June 11, 2002
• 年：2002
• 卷：41
• 期：23
• 页码：7217 - 7223
• 全文大小：233K
• 年卷期：v.41,no.23(June 11, 2002)
• ISSN：1520-4995

文摘

DNA gyrase is a major bacterial protein that is involved in replication and transcription andcatalyzes the negative supercoiling of bacterial circular DNA. DNA gyrase is a known target for antibacterialagents since its blocking induces bacterial death. Quinolones, coumarins, and cyclothialidines have beendesigned to inhibit gyrase. Significant improvements can still be envisioned for a better coumarin-gyraseinteraction. In this work, we obtained the crystal costructures of the natural coumarin clorobiocin and asynthetic analogue with the 24 kDa gyrase fragment. We used isothermal titration microcalorimetry anddifferential scanning calorimetry to obtain the thermodynamic parameters representative of the molecularinteractions occurring during the binding process between coumarins and the 24 kDa gyrase fragment.We provide the first experimental evidence that clorobiocin binds gyrase with a stronger affinity thannovobiocin. We also demonstrate the crucial role of both the hydroxybenzoate isopentenyl moiety andthe 5'-alkyl group on the noviose of the coumarins in the binding affinity for gyrase.