Metallo-Peptides: Arming Cyclic Peptide Antibiotics with New Weapons to Combat Antimicrobial Resistance

金属肽：用新武器武装环肽抗生素以对抗抗菌素耐药性

• 批准号: EP/Z533026/1
• 负责人: Sarah Barry
• 金额: $ 19.11万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ533026%2F1
• 关键词: Metallo; Peptides; Arming; Cyclic; Peptide

Microbial non-ribosomal cyclic peptides (NRcPs) such as colistin, vancomycin and daptomycin represent a major class of clinically vital antibiotics that underpin our healthcare. However, antimicrobial resistance against these critical drugs could soon render them useless, creating a devastating global health crisis. ESKAPE pathogens in particular, already pose a serious health threat worldwide as they exhibit multiple antimicrobial resistance (AMR) mechanisms. Thus, we urgently need new classes of antibiotics with novel mechanisms of action to combat AMR.Our approach to tackle AMR is to develop a new class of dual warhead metallo-peptide antibiotics by linking NRcP antibiotics to metal complexes. Conjugation of the two entities will expand the chemical space to be explored in NRcP derivatives and result in one or more gains of function of the metallo-peptides over their constituent parts e.g. novel mechanisms of action, improved selectivity. While, metal complexes are successfully used in cancer treatment and imaging diagnostics they are largely absent from antimicrobial therapy. Thus, a potentially powerful weapon against AMR has been neglected. This proposal is made possible by the previous work of the multidisciplinary team from King's College London and the Francis Crick Institute in the investigation and development of novel synthetic methods towards NRcPs and new to nature antibiotic metal complexes. We will use our extensive preliminary work to enable the development of a "mix and match" platform to create and test metallo-peptide libraries. This proposal thus represents a genuinely innovative direction in antimicrobial therapy to tackle the AMR crisis.

微生物非核糖体环肽（nrcp），如粘菌素，万古霉素和达托霉素是临床重要抗生素的主要类别，支持我们的医疗保健。然而，对这些关键药物的抗菌素耐药性可能很快使它们变得无用，从而造成毁灭性的全球健康危机。特别是ESKAPE病原体，由于它们表现出多种抗菌素耐药性机制，已经在全球范围内构成严重的健康威胁。因此，我们迫切需要具有新型作用机制的新型抗生素来对抗抗生素耐药性。我们解决AMR的方法是通过将NRcP抗生素与金属配合物连接，开发一类新的双弹头金属肽抗生素。这两个实体的偶联将扩大NRcP衍生物的化学空间，并导致金属肽在其组成部分上的一个或多个功能增益，例如新的作用机制，提高的选择性。虽然金属配合物成功地用于癌症治疗和成像诊断，但它们在抗菌治疗中基本上是缺席的。因此，一个潜在的对抗抗菌素耐药性的强大武器被忽视了。这一建议是由伦敦国王学院和弗朗西斯克里克研究所的多学科团队在研究和开发新的nrcp合成方法和新的天然抗生素金属配合物方面的先前工作实现的。我们将利用我们广泛的前期工作来开发一个“混合和匹配”平台，以创建和测试金属肽库。因此，这一建议代表了解决抗生素耐药性危机的抗菌治疗的真正创新方向。