Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2300 RA Leiden, Netherlands.
Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, 53113 Bonn, Germany.
Sci Transl Med. 2024 Aug 7;16(759):eabo4736. doi: 10.1126/scitranslmed.abo4736.
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 (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 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.
革兰氏阳性菌感染是一个主要的临床挑战，其中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解决这个问题，例如临床上使用的替拉万古，它具有增强的抗菌效力，但也引起了毒性问题。因此，仍需要具有增强的抗菌活性和改善的安全性特征的糖肽抗生素。我们描述了一类具有高度活性的半合成糖肽抗生素，即胍基脂糖肽的开发，其含有带可变脂质基团的正电荷胍基部分。这些糖肽对一组革兰氏阳性菌表现出增强的体外活性，包括临床相关的耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素菌株，对真核细胞的毒性最小，且不易产生耐药性。从机制上讲，胍基脂糖肽与细菌细胞壁前体脂质 II 结合的亲和力高于万古霉素。与野生型 d-Ala-d-Ala 脂质 II 和万古霉素耐药的 d-Ala-d-Lac 变体的结合均得到了证实，这为胍基脂糖肽对万古霉素耐药分离株增强活性提供了依据。胍基脂糖肽 EVG7 的体内疗效在小鼠大腿感染模型和 7 天败血症存活研究中进行了评估，结果均优于万古霉素。此外，在超治疗剂量下，EVG7 对肾脏的影响最小到轻度，表明与万古霉素相比，其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用于治疗临床相关多药耐药革兰氏阳性感染的抗菌药物的候选药物。
