Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains,ACS Infectious Diseases

当前位置： X-MOL 学术 › ACS Infect. Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-08-13 , DOI: 10.1021/acsinfecdis.1c00318
Emma van Groesen ₁ , Cornelis J Slingerland ₁ , Paolo Innocenti ₁ , Milos Mihajlovic ₂ , Rosalinde Masereeuw ₂ , Nathaniel I Martin ₁

Affiliation

Vancomycin functions by binding to lipid II, the penultimate bacterial cell wall building block used by both Gram-positive and Gram-negative species. However, vancomycin is generally only able to exert its antimicrobial effect against Gram-positive strains as it cannot pass the outer membrane (OM) of Gram-negative bacteria. To address this challenge, we here describe efforts to conjugate vancomycin to the OM disrupting polymyxin E nonapeptide (PMEN) to yield the hybrid “vancomyxins”. In designing these hybrid antibiotics, different spacers and conjugation sites were explored for connecting vancomycin and PMEN. The vancomyxins show improved activity against Gram-negative strains compared with the activity of vancomycin or vancomycin supplemented with PMEN separately. In addition, the vancomyxins maintain the antimicrobial effect of vancomycin against Gram-positive strains and, in some cases, show enhanced activity against vancomycin-resistant strains. The hybrid antibiotics described here have reduced nephrotoxicity when compared with clinically used polymyxin antibiotics. This study demonstrates that covalent conjugation to an OM disruptor contributes to sensitizing Gram-negative strains to vancomycin while retaining anti-Gram-positive activity.

中文翻译：

Vancomyxins：万古霉素-多粘菌素九肽偶联物，保留抗革兰氏阳性活性，增强抗革兰氏阴性菌株的效力

万古霉素通过与脂质 II 结合发挥作用，脂质 II 是革兰氏阳性菌和革兰氏阴性菌使用的倒数第二个细菌细胞壁构件。然而，万古霉素通常只能对革兰氏阳性菌株发挥抗菌作用，因为它不能通过革兰氏阴性菌的外膜 (OM)。为了应对这一挑战，我们在此描述了将万古霉素与破坏 OM 的多粘菌素 E 九肽 (PMEN) 结合以产生混合“万古霉素”的努力。在设计这些混合抗生素时，探索了用于连接万古霉素和 PMEN 的不同间隔区和结合位点。与万古霉素或单独补充有 PMEN 的万古霉素的活性相比，万古霉素对革兰氏阴性菌株的活性有所提高。此外，万古霉素保持万古霉素对革兰氏阳性菌株的抗菌作用，在某些情况下，对万古霉素耐药菌株显示出增强的活性。与临床使用的多粘菌素抗生素相比，此处描述的混合抗生素降低了肾毒性。该研究表明，与 OM 干扰物的共价结合有助于使革兰氏阴性菌株对万古霉素敏感，同时保留抗革兰氏阳性活性。

更新日期：2021-09-10

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11