Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be a cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed to overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics with enhanced antibacterial activities and improved safety profiles are still necessary. We describe the development of a class of highly potent semisynthetic glycopeptide antibiotics, the guanidino lipoglycopeptides, which contain a positively charged guanidino moiety bearing a variable lipid group. These glycopeptides exhibited enhanced in vitro activity against a panel of Gram-positive bacteria including clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains, showed minimal toxicity toward eukaryotic cells, and had a low propensity for resistance selection. Mechanistically, guanidino lipoglycopeptides engaged with bacterial cell wall precursor lipid II with a higher binding affinity than vancomycin. Binding to both wild-type d -Ala- d -Ala lipid II and the vancomycin-resistant d -Ala- d -Lac variant was confirmed, providing insight into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant isolates. The in vivo efficacy of guanidino lipoglycopeptide EVG7 was evaluated in a S. aureus murine thigh infection model and a 7-day sepsis survival study, both of which demonstrated superiority to vancomycin. Moreover, the minimal to mild kidney effects at supratherapeutic doses of EVG7 indicate an improved therapeutic safety profile compared with vancomycin. These findings position guanidino lipoglycopeptides as candidates for further development as antibacterial agents for the treatment of clinically relevant multidrug-resistant Gram-positive infections.

中文翻译：

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具有有效体外和体内抗菌活性的半合成胍基脂糖肽


革兰氏阳性细菌感染是一项重大的临床挑战，耐甲氧西林和万古霉素的菌株仍然令人担忧。近年来，已经开发出半合成万古霉素衍生物来克服这个问题，临床上使用的特拉万星就是一个例子，它表现出增强的抗菌效力，但也引起了毒性问题。因此，仍然需要具有增强抗菌活性和改善安全性的糖肽抗生素。我们描述了一类高效半合成糖肽抗生素的开发，即胍基脂糖肽，其含有带有可变脂质基团的带正电荷的胍基部分。这些糖肽对一组革兰氏阳性细菌（包括临床相关的耐甲氧西林金黄色葡萄球菌（MRSA）和万古霉素耐药菌株）表现出增强的体外活性，对真核细胞显示出最小的毒性，并且具有较低的耐药选择倾向。从机制上讲，胍基脂糖肽与细菌细胞壁前体脂质 II 的结合亲和力高于万古霉素。证实了与野生型 d-Ala- d-Ala 脂质 II 和万古霉素抗性 d-Ala- d-Lac 变体的结合，从而深入了解胍基脂糖肽对万古霉素抗性分离株的增强活性。在金黄色葡萄球菌鼠大腿感染模型和 7 天脓毒症生存研究中评估了胍基脂糖肽 EVG7 的体内功效，这两项研究均证明优于万古霉素。此外，超治疗剂量的 EVG7 的肾脏影响极小至轻微，表明与万古霉素相比，治疗安全性有所改善。 这些发现使胍基脂糖肽成为进一步开发抗菌剂的候选药物，用于治疗临床相关的多重耐药革兰氏阳性感染。