Grant: Discovery Grants Program - Individual

The cell envelope can be targeted by drugs and contaminants. Notably, cationic host defense peptides (cHDPs), part of the immune defense system, are known to damage bacterial cell membranes. They inspire the development of new antibiotics less prone to induce resistance - a global critical issue. Some cHDPs display anticancer and algicidal activity, potentially aiding tumor therapy, and offering an environmentally friendly solution against red tides induced by toxic microalgae, which can threaten crucial species in Canadian aquaculture. The role of the entire cell wall constituents in the cHDPs' cell interaction needs to be investigated. Thus, we must develop methodologies to acquire the fundamental knowledge on their action mechanism and to exploit their bioactive properties. Solid-state nuclear magnetic resonance (ssNMR) is a non-invasive technique that can reveal nanoscopic details on molecular interactions in intact cells. This emerging approach, however, faces major challenges: providing structural and dynamic information from crowded spectra recorded on cell samples with limited lifespan. Faster experiments with improved resolution are thus urgently needed to provide molecular information that cannot be obtained otherwise. Our research program aims to refine and advance methodological approaches for characterizing intact cells and their interactions by ssNMR. Specifically, for the next 5 years, we intend to: (1) enhance and diversify the stable isotopic labeling, which highlights specific cell components and improves signal sensitivity; (2) develop strategies to determine distances between peptides and the membrane lipids in cellulo; and (3) refine in-cell methodologies for studying interactions with the cell wall. To do so, we will pursue a transversal objective: shedding light on the antimicrobial, anticancer and algicidal activity of cHDPs by studying their action on bacteria, cancer cells and microalgae. The long-term objective of our program is to expand our ssNMR approaches to study molecular interactions with higher organisms. By providing novel approaches to tackle the complex molecular interactions of cells, our transformative research program should lead to significant breakthroughs in the field of biological ssNMR. Moreover, the methods we will establish will be applicable to non-peptide ligands, including synthetic drugs and aquatic contaminants. They will be important in several domains, thus fostering collaboration with the pharmaceutical and environmental sectors, as well as interdisciplinary academic research. The knowledge gained on the biological activity and cell specificity of cHDPs could trigger the conception of novel, safe and targeted therapeutic approaches, and impact the pharmaceutical innovation pipeline in Canada. Our study of algicidal cHDPs could help offer sustainable solutions for managing red tides in the context of global warming, of great importance for aquacultors and policy makers.