Probing the Limits of Antimicrobial Peptide-Siderophore Uptake to Gram-Negative Bacteria: A Nisin-Desferrioxamine B Bioconjugate with Antimicrobial Activity Against Pseudomonas Aeruginosa

Developing new classes of antimicrobials that are active against Gram-negative bacteria is vital to combat the rising threat of antimicrobial resistance. “Trojan Horse” strategies, where antibiotics are conjugated to siderophores to enable penetration of the outer membrane of Gram-negative bacteria by hijacking the iron-siderophore transport pathways, are emerging as a powerful method to deliver small molecule antibiotics. In this work we have developed a synthetic route to nisin-desferrioxamine B bioconjugates incorporating a cleavable trimethyl lock linker. This antimicrobial peptide-siderophore bioconjugate is active against Pseudomonas aeruginosa, which is particularly resistant to the penetration of most classical antibiotics and antimicrobial peptides. We have shown that the mechanism of action is siderophore dependent: to our knowledge this is the first time that an antibiotic-siderophore bioconjugate has been used to successfully deliver an antimicrobial peptide cargo of this size and complexity to Gram-negative bacteria.