Engineering antibacterial cationic amphipathic peptidomimetics for targeting biofilm-embedded and intracellular bacteria – AmphiPep

In order to develop different types of amphipathic molecular architectures able to reach bacteria sanctuarized in biofilm or inside cells, we have chosen peptoid-type peptidomimetics whose intrinsic properties enable the custom design of various secondary structures just by side-chains modulation, a unique feature in the field of foldamers. Research hypotheses are based on i) the potential of peptoid-type peptidomimetics as future therapeutics and particularly as antibacterial agents, ii) new efficient tools to control the secondary structure of peptoid oligomers that are otherwise very flexible and iii) recent promising results obtained concerning short triazolium-based peptoid oligomers. The project is divided into four interconnected scientific work packages devoted to the design, synthesis and conformational analysis of various amphipathic architectures, evaluation of their activities on planktonic multi-resistant pathogens but also their capacity to target biofilm-embedded and/or intracellular bacteria and the understanding of their mechanisms of action using biophysical and genomic approaches. To achieve these objectives, the AmphiPep project consortium comprises organic chemists, specialists in peptoid-type peptidomimetics and foldamers (ICCF), microbiologists (LMGE and CIRI) with strong expertise in the field of biofilms of microorganisms linked to health and in particular in the field of osteoarticular infections due to staphylococci, and biophysicists, experts in the mechanisms of action of membrane-active peptides.

The research works have begun the 1st January 2021

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Critical challenges remain in the battle against infectious diseases. The emergence of antimicrobial resistances is not the unique serious threat for patients. Infections associated with bacterial specific lifestyles such as sanctuarization in biofilm or inside cells, are also difficult-to-treat with currently available antibiotics. Indeed, these two types of protection developed by pathogenic bacteria are responsible for treatment failure and development of most chronic infectious diseases, notably recurrent urinary tract and osteoarticular infections. Therefore, there is not only a need to develop novel antibacterial agents but also to characterize molecules able to target bacteria embedded in biofilms and those with intracellular growth. The AmphiPep project aims at addressing these critical issues through a bio-inspired approach.
Antimicrobial peptides have gained increased attention due to their broad-spectrum activities with low emergence of resistance; but their therapeutic use is hampered by unwanted toxicity, poor pharmacokinetics and high cost. Nevertheless, natural AMPs are a great source of inspiration for the development of a safe and efficient new generation of antimicrobial agents. Notably, many peptidomimetics have been designed to exhibit the cationic amphipathic helical secondary structure of native AMPs, which is the key determinant of their activity by interaction with bacterial membranes. Previous studies suggest that the shape of the amphipathic oligomer can dramatically influence the mode of interaction with membranes and therefore the mechanism of action. The AmphiPep project proposes to develop a variety of well-defined amphipathic architectures in order to evaluate the impact of the shape on the antibacterial activity towards planktonic, biofilm-embedded or intracellular bacteria as well as on selectivity. To access different types of amphipathic architectures, we have chosen peptoid-type peptidomimetics whose intrinsic properties enable the custom design of various secondary structures just by side-chains modulation, a unique feature in the field of foldamers. Research hypotheses are based on i) the potential of peptoid-type peptidomimetics as future therapeutics and particularly as antibacterial agents, ii) new efficient tools to control the secondary structure of peptoid oligomers that are otherwise very flexible and iii) recent promising results obtained concerning short triazolium-based peptoid oligomers. The project is divided into four interconnected scientific work packages devoted to the design, synthesis and conformational analysis of various amphipathic architectures, evaluation of their activities on planktonic multi-resistant pathogens but also their capacity to target biofilm-embedded and/or intracellular bacteria and the understanding of their mechanisms of action using biophysical and genomic approaches.