Dissecting ramoplanin: Mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics
Dissecting ramoplanin: Mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics
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DOI：
10.1021/ja047879t
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发表时间：
2004-06-23
影响因子：
15
通讯作者：
Walker, S
中科院分区：
文献类型：
--
作者：
Chen, L;Yuan, YQ;Walker, S
Ramoplanin是一种有效的环脂糖沉积肽抗生素，通过与肽聚糖中间体脂质II结合并阻断其聚合形成肽聚糖的碳水化合物链，从而破坏细菌细胞壁的合成。虽然拉莫planin是一种很有前途的化合物，但它有局限性，妨碍静脉给药进行全身使用。然而，有可能用类似物克服这些限制。在这篇文章中，我们剖析了结构变化对拉莫planin的影响。本文描述的研究将全合成与酶动力学、核磁共振分析和MIC测量相结合，揭示了这种抗生素在脂质II结合、转糖基化抑制和生物活性中的关键结构特征的作用。该结果可作为设计具有更好生物学性能的合成可及类似物的基础。
Ramoplanin is a potent cyclic lipoglycodepsipeptide antibiotic that disrupts bacterial cell wall synthesis by binding to the peptidoglycan intermediate Lipid II and blocking its polymerization to form the carbohydrate chains of peptidoglycan. Although ramoplanin is a promising compound for certain indications, it has limitations that impede IV administration for systemic use. However, it may be possible to overcome these limitations with analogues. In this manuscript, we dissect the effects of structural changes to ramoplanin. The studies described here combine total synthesis with enzyme kinetics, NMR analysis, and MIC measurements to shed light on the roles of key structural features in this antibiotic in Lipid II binding, transglycosylation inhibition, and biological activity. The results should serve as a foundation for the design of synthetically accessible analogues with improved biological properties.