Antimicrobial Peptides and their Interactions with Model Membranes - Structure and Dynamics
How are antimicrobial peptides (AMPs) able to kill bacterial pathogens so efficiently, often without generating significant resistance? Next, how can these natural compounds and their derivatives be utilized as therapeutics? These are the main questions we will address in this project. Although almost 30 years of research suggests that most AMPs disrupt or destabilize the cytoplasmic membrane, a full understanding of the fundamental mechanistic mode of action at the molecular level is still lacking. This lack of knowledge together with the common toxicity and sensitivity towards (in some cases, bacteria-induced) enzymatic degradation are major obstacles preventing their use for therapeutic purposes.
Here we use X-ray and neutron scattering as a main tool to investigate the mechanism(s) of antimicrobial peptides. We will develop a set of techniques mainly based on neutron and X-ray scattering. We will use hydrogen/deuterium contrast variation trick to investigate the structure, dynamics as well as induced transport in peptide/lipid model membranes. We thereby expect to create a solid methodological platform, to gain profound insight into the molecular mechanism. Next, based on insight into the physico-chemical properties and key parameters determining peptide-lipid interaction, we design new peptides and peptidomimetic molecules with significantly less toxicity and increased proteloytic stability. This will be achieved by both modifying peptides through polymer conjugation schemes as well as through developing antimicrobial peptoids, a class of peptidomimetics.
This project is a joint NordForsk project with Prof. Håvard Jenssen (University of Roskilde), Prof. Paul Robert Hansen (University of Copenhagen) and Marité Cárdenas (University of Malmø).
- PhD student Josefine Eilsø Nielsen
- PhD student Victoria Ariel Bjørnestad
- MSc. student Mirna Porobic
- J.E. Nielsen, V.A.. Bjørnestad,, and R. Lund, “Resolving the structural interactions between antimicrobial peptides and lipid membranes using small-angle scattering methods: the case of indolicidin.”Soft Matter, 2018, 11, 37–14.
- Xu, D. et al. Toward hemocompatible self-assembling antimicrobial nanofibers: understanding the synergistic effect of supramolecular structure and PEGylation on hemocompatibility. RSC Adv. 6, 15911–15919 (2016).
- Xu, D. et al. Designed supramolecular filamentous peptides: balance of nanostructure, cytotoxicity and antimicrobial activity. Chem. Commun. 51, 1289–1292 (2014).