Background

Recently, through comprehensive medicinal chemistry efforts, we have found a new daptomycin analogue, termed kynomycin, showing enhanced activity against both methicillin-resistant S. aureus and vancomycin-resistant Enterococcus in vitro and in vivo, with improved pharmacokinetics and lower cytotoxicity than daptomycin.

Methods

In this study we compared the physicochemical properties of kynomycin with those of daptomycin from an atomic perspective by using Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations.

Results and conclusion

We observed that kynurenine methylation changes daptomycin's key physicochemical properties; its calcium dependent oligomerization efficiency is improved and the modified kynurenine strengths contacts with the lipid tail and tryptophan residues. In addition, it is observed that, compared to daptomycin, kynomycin tetramer is more stable and binds stronger to calcium. The combined experiments provide key clues for the improved antibacterial activity of kynomycin.

General significance

We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics.

中文翻译：

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提高达托霉素活性的原子视角

背景

最近，通过全面的药物化学研究，我们发现了一种新的达托霉素类似物，称为犬霉素，在体外和体内对耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌均表现出增强的活性，与达托霉素相比，具有更好的药代动力学和更低的细胞毒性。

方法

在这项研究中，我们通过使用核磁共振光谱和分子动力学模拟从原子角度比较了犬霉素和达托霉素的理化性质。

结果与结论

我们观察到犬尿氨酸甲基化改变了达托霉素的关键理化特性；其钙依赖性寡聚化效率得到提高，并且修饰的犬尿氨酸强度与脂质尾部和色氨酸残基接触。此外，据观察，与达托霉素相比，犬霉素四聚体更稳定，与钙的结合更强。联合实验为提高犬霉素的抗菌活性提供了关键线索。

一般意义

我们预计这种方法将有助于研究新型钙依赖性肽抗生素的钙结合和寡聚化特征。