Colistin, vancomycin, and daptomycin—three of the last-resort antibiotics—are being chemically strapped to metal complexes to create a new class of dual-warhead drugs. These microbial non-ribosomal cyclic peptides (NRcPs) are clinically vital, but ESKAPE pathogens are already evolving resistance to them through multiple mechanisms. If resistance spreads, these drugs could become useless, leaving doctors with few options for severe bacterial infections. The research team at King’s College London and the Francis Crick Institute aims to build a “mix and match” platform that links existing NRcP antibiotics to metal complexes—compounds largely absent from antimicrobial therapy despite their success in cancer treatment and imaging. The goal is to give the resulting metallo-peptides novel mechanisms of action and improved selectivity that their separate parts lack. If the platform works, it could generate libraries of new antibiotics that bypass existing resistance mechanisms, buying time before the next wave of resistance emerges. This is fundamental science with a clear translational target: keeping the antibiotics that underpin modern medicine—from surgery to chemotherapy—effective for longer.
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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.
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