Multi-mode imaging to underpin a drug development pipeline for a new, peptide class of antibiotics

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Successful therapy of a bacterial lung infection using a bactericidal AMP delivered i.v. is extremely rare. Indeed, of thirty-six AMPs known to have entered clinical or preclinical studies, only seven are or were being developed for i.v. delivery (three discontinued) and none are thought to act in vivo using a direct antibacterial mechansism. The pathway for successful development of this new classs of antibiotics is therefore far from clear with new approaches needed to understand pharmacokinetics (PK), biodistribution and pharmacodynamics (PD), the origin of any toxicity, interactions with the innate immune system and the ability of this class to eradicate intracellular bacteria which are increasingly suspected as being the cause of clinical failure, relapses and resistance after antibiotic therapy.We propose that a multi-mode imaging approach is the key to addressing these substantial barriers. Specifically, this project aims to produce and characterise a panel of differently labelled AMP analogues that will enable in vitro and in vivo fluorescence imaging and in vivo radiopharmaceutical tracing. Attaching rhodamine or its derivatives to the AMP leads, using solid-phase synthesis, will enable the study of (co)localisation of the peptides in epithelial cells, macrophage and neutrophil to understand the mechanisms of any cytotoxicity, impact on cytokine release and ability to reach intracellular pathogens. Near-infrared (700-900 nm) fluorescent labels will enable time-resolved biodistribution studies of AMP delivered i.v. or via dry-powder insufflation to the lung. Labelling AMPs for PET imaging with 68Ga, via a conjugated hexadentate HydrOxyPyridinOne (HOPO) chelator, will increase sensitivity, enable time-resolved studies of infection resolution and may lead to a selective but non-specific means of