The World Health Organization (WHO) has reported that multidrug-resistant (MDR) bacteria cause 1.27 million deaths yearly worldwide. The yearly mortality rates are estimated to increase to 10 million in 2050 if no action is taken to develop new antibiotic formulations*. Colistin, belonging to the class of antimicrobial peptides, is an effective antibiotic for many different gram-negative bacteria but is also found to be toxic to the kidneys. If colistin’s toxicity issues can be resolved, it could be an effective option to combat MDR bacteria. One of these options could be in the form of encapsulation. The research team already investigated how colistin can be combined with PEO-b-PMAA block copolymers to create nanoparticles, known as complex coacervate core micelles (C3Ms), in which colistin is effectively encapsulated and protected.**

This HALRIC pilot project aims to elucidate the detailed internal structure of the nanoparticles and its dynamics by using small-angle neutron scattering (SANS) at large-scale infrastructures in combination with small-angle X-ray scattering (SAXS) and dynamic light scatttering (DLS) at local infrastructures at  Aarhus University (AU) and the University of Oslo (UiO). The structure and exchange kinetics, i.e., the lifetime of a single component in micelles, are important characteristics for a better pharmacologic understanding. Through the collaboration of SAXS/SANS modelling expertise between AU and UiO, the pilot project team will analyze these structures in detail using an (unpublished) core-shell SAXS/SANS model that will be specially developed for this project.

In previous work at UiO, the researchers demonstrated that these micelles are well-defined and stable. In the micelles, the positively charged colistin and the negatively charged PMAA form the core, while the PEO forms an outer protective shell. Using SAXS, the researchers elucidated the general structure and composition of these C3Ms but could neither resolve the internal structure nor the distribution of the drug, which inspired the work that is now carried out in this HALRIC pilot project.

For further information about this HALRIC pilot project, please contact:

Thomas Vogelaar
t.d.vogelaar@kjemi.uio.no

References:

* Tacconelli, E.; Carrara, E.; Savoldi, A.; Harbarth, S.; Mendelson, M.; Monnet, D. L.; Pulcini, C.; Kahlmeter, G.; Kluytmans, J.; Carmeli, Y.; Ouellette, M.; Outterson, K.; Patel, J.; Cavaleri, M.; Cox, E. M.; Houchens, C. R.; Grayson, M. L.; Hansen, P.; Singh, N.; Theuretzbacher, U.; Magrini, N. et al. Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18 (3), 318–327. https://doi.org/10.1016/S1473-3099(17)30753-3.

** Vogelaar, T.D.; Agger, A.E.; Reseland, J.E.; Linke, D.; Jenssen, H.; Lund, R. Crafting Stable Antibiotic Nanoparticles via Complex Coacervation of Colistin with Block Copolymers. Biomacromolecules. 2024. https://doi.org/10.1021/acs.biomac.4c00337.