Polymeric Analogues of Antimicrobial Peptides with Therapeutic Potential against Clostridium difficile – Therapeptics

THERAPEPTICS is a bio-inspired chemistry project which aims at synthesizing new amino-acid polymers, called peptidomimetics, as simplified analogues of natural antimicrobial peptides (AMPs). The main objective of this project is to study their antibiotic potential against the bacterium Clostridium difficile, leading cause of intestinal nosocomial post-antibiotic infections in occidental countries.
Peptidomimetics will be made out of N-alkylated amino-acid derivatives, prepared from natural amino-acid building blocks, as a quite attractive alternative to petrochemistry. Cyclized into N-carboxyanhydride monomers, these derivatives will lead to original polymers by using a ring opening polymerization (ROP) strategy, a cost-efficient way to synthesize polypeptides, as compared to solid phase peptide synthesis. To mimic the composition of natural AMPs, the structure of the copolymeric analogues will include cationic (C) and hydrophobic (H) amino-acids. The optimal C/H ratio, searching for efficient and selective antibiotics, will be investigated, along with the influence of the polymerization degree toward the biological activity profile. The N-alkylation of amino-acids should prevent from the degradation of the polymers into the digestive tract, allowing oral administration. A macrocyclic version of the best antibiotic polymers will finally be synthesized, involving either a N-heterocyclic carbene catalysis pathway or a post-polymerization ring closure approach.
Such macromolecules appear as quite innovative scaffolds for designing novel antibiotics of local use (oral route with low systemic exposure or topical route for example) and presenting new mechanisms of action, to try to bypass the bacterial resistance pathways, possibly impacting both the therapeutic management of some major nosocomial infections and the renewing of the anti-infective arsenal developed by the pharmaceutical industry.