Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia.
ChemMedChem. 2020 Aug 5;15(15):1429-1438. doi: 10.1002/cmdc.202000033. Epub 2020 Jun 12.
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.
目前的抗生素研究状况需要迫切发明针对多药耐药菌的新型药物。世界卫生组织根据对抗生素的新需求的迫切程度，将抗生素耐药菌分为关键、高和中等优先级。天然存在的尿嘧啶衍生的“核苷类抗生素”通过抑制尚未在临床环境中探索的跨膜蛋白 MraY（移位酶 I），对多种优先耐药生物体表现出有希望的活性。MraY 的催化活性是细菌细胞活力和生长的必要过程，包括优先生物体的活力和生长。Muraymycins 是天然存在的 MraY 抑制剂的一个子类。尽管具有很强的抗生素特性，但 muraymycins 的结构复杂性主张简化类似物作为潜在的先导结构。在此，我们报告了丝氨酸模板连接的简化 muraymycin 型类似物的系统结构-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天然存在的 muraymycins 的复杂结构可以很容易地简化为针对耐药优先生物体的生物活性支架。这项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铺平道路。
