Studies on daptomycin lactam-based analogues,Journal of Peptide Science

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Studies on daptomycin lactam-based analogues
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-06-29 , DOI: 10.1002/psc.3430
Hoi Yee Chow ₁ , Kathy Hiu Laam Po ₂ , Sheng Chen ₂ , Xuechen Li ₁

Affiliation

Herein, we report the synthesis and antibacterial evaluation of a series of daptomycin lactam-based analogues. As compared with daptomycin, the daptomycin analogue with singly modified lactam has an eightfold increase in its minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus. Incorporating effective modifications found in previous daptomycin structure–activity relationship studies to produce lactam-based analogues with multiple modifications did not improve the antibacterial activity of the analogues. Instead, the antibacterial activity was greatly reduced when a rather rigid 4-(phenylethynyl)benzoyl group replaced the flexible n-decanoyl group. The fact that the lactam analogue with the 4-(phenylethynyl)benzoyl group did not exhibit the antibacterial activity comparable to the two respective singly modified analogues showed that the inactivity was probably due to the deviation from the active conformation. This series of lactam analogues may generate insights on the importance of studying the active conformation of daptomycin and how the structural modifications affect the active conformation.

中文翻译：

达托霉素内酰胺类类似物的研究

在此，我们报告了一系列基于达托霉素内酰胺的类似物的合成和抗菌评估。与达托霉素相比，单修饰内酰胺的达托霉素类似物对耐甲氧西林金黄色葡萄球菌的最低抑菌浓度（MIC）提高了八倍。结合先前达托霉素构效关系研究中发现的有效修饰来生产具有多种修饰的内酰胺类类似物并不能提高类似物的抗菌活性。相反，当相当刚性的 4-(苯乙炔基)苯甲酰基取代柔性n时，抗菌活性大大降低-癸酰基。具有 4-(苯乙炔基)苯甲酰基的内酰胺类似物没有表现出与两种单独修饰的类似物相当的抗菌活性这一事实表明，这种非活性可能是由于偏离了活性构象。这一系列的内酰胺类似物可能会对研究达托霉素活性构象的重要性以及结构修饰如何影响活性构象产生见解。

更新日期：2022-06-29

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