Isolation, Structure, and Antibacterial Activity of Philipimycin, A Thiazolyl Peptide Discovered from Actinoplanes philippinensis MA7347

详细信息    查看全文

• 作者：Chaowei Zhang ; James Occi ; Prakash Masurekar ; John F. Barrett ; Deborah L. Zink ; Scott Smith ; Russell Onishi ; Sookhee Ha ; Oscar Salazar ; Olga Genilloud ; Angela Basilio ; Francisca Vicente ; Charles Gill
• 刊名：Journal of the American Chemical Society
• 出版年：2008
• 出版时间：September 10, 2008
• 年：2008
• 卷：130
• 期：36
• 页码：12102-12110
• 全文大小：325K
• 年卷期：v.130,no.36(September 10, 2008)
• ISSN：1520-5126

文摘

Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against Gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 μg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED₅₀ value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro₂₃, Pro₂₂, and Pro₂₆ of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.