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

微生物非核糖体环肽(NRCP)，如粘菌素、万古霉素和达托霉素，代表着一类重要的临床重要抗生素，支撑着我们的医疗保健。然而，对这些关键药物的抗菌素耐药性可能很快就会使它们变得毫无用处，造成毁灭性的全球健康危机。尤其是ESKAPE病原体，已经在世界范围内构成了严重的健康威胁，因为它们表现出多种抗菌素耐药(AMR)机制。因此，我们迫切需要具有新的作用机制的新型抗生素来对抗AMR。我们解决AMR的方法是通过将NRCP抗生素与金属络合物连接起来，开发一类新的双弹头金属多肽抗生素。这两个实体的结合将扩大NRCP衍生物中有待探索的化学空间，并导致金属多肽相对于其组成部分的一个或多个功能收益，例如新的作用机制，提高的选择性。虽然金属络合物被成功地应用于癌症治疗和影像诊断，但它们在抗菌治疗中基本上是缺席的。因此，针对AMR的一种潜在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先前在研究和开发针对NRCP和新的自然抗生素金属络合物的新合成方法时所做的工作。我们将利用我们广泛的前期工作来开发一个“混合匹配”平台来创建和测试金属多肽文库。因此，这项建议代表了抗菌素治疗的一个真正创新的方向，以应对AMR危机。

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.