Adapting antibacterial display to identify serum active macrocyclic peptide antibiotics.
Adapting antibacterial display to identify serum active macrocyclic peptide antibiotics.
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采用抗菌显示来识别血清活性大环肽抗生素。
DOI：
10.1101/2023.07.28.550711
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Davies,BryanW
中科院分区：
文献类型：
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作者：
Randall,JustinR;Groover,KyraE;O'Donnell,AngelaC;Garza,JosephM;Cole,TJeffrey;Davies,BryanW
许多抗生素耐药性感染缺乏可用的治疗方法，这凸显了抗生素发现创新的迫切需要。肽是一种未得到充分重视的抗生素支架，因为它们通常具有蛋白水解不稳定性和对人类细胞的毒性，使得体内使用具有挑战性。为了研究与血清活性相关的序列因素，我们采用抗菌展示技术直接在人血清中筛选具有抗菌潜力的肽大环化合物库。我们确定了几十个新的大环肽抗生素序列，并发现在我们的库中的血清活性受到肽长度，阳离子电荷和存在的二硫键的数量的影响。有趣的是，我们最具活性的先导肽的优化版本渗透革兰氏阴性菌的外膜，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微生物肽形成对比，传统的阳离子抗微生物肽通过溶解两种细菌膜而快速杀死。值得注意的是，这种优化的变体对哺乳动物细胞没有毒性，并保留了其在体内的功能，这表明了治疗前景。我们的研究结果支持使用更多的生理相关的条件时，筛选肽的抗微生物活性，保留在体内的功能。
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.