UC Davis

All living cells are enclosed by biological membranes, comprising of lipid bilayers formed by self-assembly of phospholipids, membrane proteins, cholesterol etc. Membrane active peptides (MAPs) are peptides that interact with the lipid bilayer, perturbing the structure and function of the biological membranes, impacting the function of the living cells. Antimicrobial peptides (AMPs), are a subset of MAPs that interact with pathogenic microbial membranes, disrupting the integrity of the lipid bilayer, using mechanisms such as pore formation, resulting in membrane leakage and cell death. Since MAPs interact directly with cell membranes, they are becoming increasingly important as a possible solution to multi-drug resistant pathogens. Multi-drug resistant fungal infections due to opportunistic and pathogenic fungi are one of the most common infections in the world. Millions of people across the globe are affected by these infections and about 1.5 million people each year succumb to this disease. Amphotericin B and azole drugs such as fluconazole and ketoconazole are common anti-fungal agents that have been used for many years but have a variety of short-term and long-term side effects and have induced widespread resistance in fungi. Therefore, there is dire need for the discovery of novel membrane active peptides with antimicrobial activities, and understanding how they interact with cell membranes. By applying this knowledge, we hope to develop highly selective antifungal membrane active peptides.In this dissertation, we report on the successful use of one-bead one-compound (OBOC) combinatorial library method to discover new MAPs with antifungal properties. To better understand the mechanism of action of these MAPs, we have used various methods to biochemically and biologically characterize these peptides.