Assembling against Resistance: Antimicrobial Nanoparticles based on Molecular Assembly

Antimcrobial resistance among pathogens, i.e. bacteria that cause disease is among the largest threats to global health in the 21st century. Antimicrobial peptides are promising agents to treat infections as they commonly act directly on the cell membrane of the bacteria without causing significant resistance. Yet, they are surprisingly little used in treatments. This is mainly because they are rather unstable in the body and make break up before reaching their targets. In addition they may have adverse effects and cause some toxicity. In this project, ANTISOFT we will focus on developing novel ways of encapsulating the drug into nanoparticles. In this way the drug is protected and the particle may release its drug only where it is needed, i.e. pathogenic bacteria. In this project we will find strategies to design efficient nanoparties and systematically test their activity towards bacteria as well as their potential toxicity against host cells.

Antimicrobial peptides (AMPs) are found in many species throughout nature to fight pathogens such as bacteria or even by bacteria themselves to fight other bacteria. Human saliva and sweat contains AMPs as a part of the innate immune system to fight infections. Some AMPs act against fungi, viruses and even tumors. These molecules have been around for hundreds of millions of years and have largely been able to avoid bacterial resistance. Yet, they are surprisingly little used in treatments – mainly because they are rather unstable towards serum proteins and may be toxic to other cells. Here we will focus on the use of peptides assemblies as a modular antimicrobial system with tunable interactions and release profiles. By understanding their self-assembly and lipid interactions, we will create a toolbox for nanostructured AMPs, i.e. ” soft matter antibiotics”. In order to utilize these compounds, research is needed in order to understand how they work and how they need to be modified to enhance stability and reduce toxicity. In this project we have gathered a multi-disciplinary team to address these challenges. By combining experts within fields of synthetic chemistry, scattering techniques and computer simulations with experts within biochemistry and molecular biology, we will create antimicrobial nanoparticles, i.e. AMP assemblies with significantly reduced toxicity and enhanced stability. We will synthesize new materials, study the assemblies in solution and near lipid model membranes in order to get insight into their mechanism of action, and we will determine the resulting stability towards proteases. Selected promising compounds will be compared towards biological function, their antimicrobial activity and toxicity towards organs using a ”organ-on-chip” approaches. From this insight, we will facilitate the design of new materials that can be used for therapeutic against growing threats of multi-resistant strains of bacteria.