TThe disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin.

The project presents an innovative chemical tool to be applied to known cyclic peptide antibiotics.

The objective consists of proving that the insertion of disulfide bonds within antimicrobial cyclic peptides improves their therapeutic window, more precisely, reduces the nephrotoxicity of antibacterials such as polymyxins (polymyxin E/colistin) and murepavadin.

The rationale of the design consists of maintaining the overall structure of the antibiotic to preserve the antibacterial activity while the presence of the disulfide bond within the peptide backbone would facilitate the initial metabolization and detoxification by oxidoreductases (decyclization of the disulfide-polymyxin/murepavadin) upon eventual accumulation of the antibiotic in the kidney.

The project follows a proof-of-concept scheme involving the necessary chemistry to prepare the disulfide-polymyxins and -murepavadin model compounds, the in vitro and in vivo assays to assess activity and low toxicity, and estimation the therapeutic window.

Finally, tests to prove the design hypothesis (the search of metabolites related to the reductive opening of the cyclic peptide to facilitate detoxification) and the mechanism of action at the membrane level are also proposed.