Peptide therapeutics are an appealing agent in the fight against multi-drug resistant bacteria. With novel mechanisms of activity with everything from enzyme inhibition to membrane permeabilization they serve as an excellent toolbox for development into novel therapeutics. Concern has been raised around resistance development to peptide antibiotics, with several examples already present in the literature it is a serious concern that needs addressing. Development of peptide-drug conjugates where a peptide has been covalently or non-covalently attached to a small molecule drug or second peptide with novel mode(s) of action, serve as a potential inhibitor to resistance development; as the target needs to develop multiple novel resistance mechanism at one time to overcome the peptide drug conjugate.
Proline rich antimicrobial peptides (PrAMPs) are a class of antimicrobial peptides which are active only against Gram-negative bacteria with multiple modes of action, with specific inhibition of the 70S ribosome and bacterial DnaK. The dule mode of action of PrAMPs, alongside their specificity towards Gram-negative bacteria, make them an excellent base for building peptide drug conjugates. Perhaps the best well studied of all PrAMPs is Oncocin, a 19mer peptide originally isolated from Oncepeltus fasciatus. The activity of Oncocin in the nuclear environment of suggests conjugation to a small molecule drug which is active in the nuclear environment, for this reason we have explored conjugation to ciprofloxacin. Ciprofloxacin is active against DNA gyrase and is suitable for use in solid phase peptide synthesis.
In this talk I will present our work towards generation of Oncocin-ciprofloxacin conjugates, the effect this has on antimicrobial properties and the potential for this strategy to be used in other applications. Peptide-drug conjugates are gaining attention in the antimicrobial space but this study represents the first of its kind using Oncocin while exploring multiple conjugation approaches for direct comparison of potency.