PDF(Pubmed)
Abstract：
The lack of available treatments for many antimicrobial-resistant infections highlights the critical need for antibiotic discovery innovation. Peptides are an underappreciated antibiotic scaffold because they often suffer from proteolytic instability and toxicity toward human cells, making in vivo use challenging. To investigate sequence factors related to serum activity, we adapt an antibacterial display technology to screen a library of peptide macrocycles for antibacterial potential directly in human serum. We identify dozens of new macrocyclic peptide antibiotic sequences and find that serum activity within our library is influenced by peptide length, cationic charge, and the number of disulfide bonds present. Interestingly, an optimized version of our most active lead peptide permeates the outer membrane of Gram-negative bacteria without strong inner-membrane disruption and kills bacteria slowly while causing cell elongation. This contrasts with traditional cationic antimicrobial peptides, which kill rapidly via lysis of both bacterial membranes. Notably, this optimized variant is not toxic to mammalian cells and retains its function in vivo, suggesting therapeutic promise. Our results support the use of more physiologically relevant conditions when screening peptides for antimicrobial activity which retain in vivo functionality.
摘要：
许多抗微生物药物耐药性感染缺乏可用的治疗方法凸显了对抗生素发现创新的关键需求。肽是一种被低估的抗生素支架，因为它们经常遭受蛋白水解不稳定性和对人类细胞的毒性。使体内使用具有挑战性。探讨与血清活性相关的序列因子,我们采用抗菌展示技术来筛选直接在人血清中具有抗菌潜力的肽大环化合物库。我们鉴定了数十种新的大环肽抗生素序列，并发现我们文库中的血清活性受肽长度的影响。阳离子电荷，和存在的二硫键的数量。有趣的是,我们最活跃的铅肽的优化版本渗透革兰氏阴性细菌的外膜而没有强烈的内膜破坏，并缓慢杀死细菌，同时引起细胞伸长。这与传统的阳离子抗菌肽形成对比，通过裂解两个细菌膜迅速杀死。值得注意的是,这种优化的变体对哺乳动物细胞无毒，并保留其在体内的功能，暗示治疗的希望。我们的结果支持在筛选保留体内功能的抗微生物活性的肽时使用更生理相关的条件。
