Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores
Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores
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DOI：
10.1002/cmdc.202000033
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发表时间：
2020-06-12
期刊：
影响因子：
3.4
通讯作者：
Rudrawar, Santosh
中科院分区：
文献类型：
--
作者：
Patel, Bhautikkumar;Kerr, Rachel, V;Rudrawar, Santosh
抗生素研究的现状要求迫切需要发明对多重耐药细菌起作用的新药物。世界卫生组织根据对新抗生素需求的紧迫性，将抗药性细菌分为严重、高度和中等优先级。天然尿苷衍生的核苷抗生素通过抑制跨膜蛋白mray(转位酶I)，对许多优先耐药的生物显示出良好的活性，这一点尚未在临床上探索。Mray的催化活性对细菌细胞的存活和生长是必不可少的过程，包括优势生物的生长。Muraymycins是自然产生的mray抑制剂的一个亚类。尽管Muraymycins具有强大的抗菌特性，但其结构的复杂性提倡将简化的类似物作为潜在的先导结构。在这里，我们报告了丝氨酸模板连接的简化的Muraymycin类似物的系统结构-活性关系(SAR)研究。这项丝氨酸模板类似物的初步SAR先导研究成功地揭示了自然产生的鼠李霉素的复杂结构可以很容易地被简化，以提供对抗耐药优先生物的生物活性支架。本研究将为基于简化丝氨酸模板的新型抗菌先导化合物的开发奠定基础。
The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. The catalytic activity of MraY is an essential process for bacterial cell viability and growth including that of priority organisms. Muraymycins are one subclass of naturally occurring MraY inhibitors. Despite having potent antibiotic properties, the structural complexity of muraymycins advocates for simplified analogues as potential lead structures. Herein, we report a systematic structure-activity relationship (SAR) study of serine template-linked, simplified muraymycin-type analogues. This preliminary SAR lead study of serine template analogues successfully revealed that the complex structure of naturally occurring muraymycins could be easily simplified to afford bioactive scaffolds against resistant priority organisms. This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template.