Isolation, Structure, and Absolute Stereochemistry of Platensimycin, A Broad Spectrum Antibiotic Discovered Using an Antisense Differential Sensitivity Strategy

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• 作者：Sheo B. Singh ; Hiranthi Jayasuriya ; John G. Ondeyka ; Kithsiri B. Herath ; Chaowei Zhang ; Deborah L. Zink ; Nancy N. Tsou ; Richard G. Ball ; Angela Basilio ; Olga Genilloud ; Maria Teresa Diez ; Francisca Vi
• 刊名：Journal of the American Chemical Society
• 出版年：2006
• 出版时间：September 13, 2006
• 年：2006
• 卷：128
• 期：36
• 页码：11916 - 11920
• 全文大小：91K
• 年卷期：v.128,no.36(September 13, 2006)
• ISSN：1520-5126

文摘

Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymesincluding the elongation enzymes, mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fattyacid synthesis is one of the new targets for the discovery and development of antibacterial agents.Platensimycin (1a) is a novel broad spectrum Gram-positive antibiotic produced by Streptomyces platensis.It was discovered by target-based whole-cell screening strategy using antisense differential sensitivity assay.It inhibits bacterial growth by selectively inhibiting condensing enzyme FabF of the fatty acid synthesispathway and was isolated by a two-step process, a capture step followed by reversed-phase HPLC. Thestructure was elucidated by 2D NMR methods and confirmed by X-ray crystallographic analysis of a bromoderivative. It was determined that potential reactivity of the enone moiety does not play a key role in thebiological activity of platensimycin. However, cyclohexenone ring conformation renders for the strongerbinding interaction with the enzyme. The isolation, structure elucidation, derivatization, and biological activityof 6,7-dihydroplatensimycin are described.