My research focuses on the identification, characterization, and engineering of novel antimicrobial agents based on structural, bioinformatics, and functional studies. Our ultimate goal is to develop novel compounds that curb pathogenic microbes, especially difficult-to-kill microbes such as methicillin-resistant Staphylococcus aureus (MRSA).
Naturally occurring antimicrobial peptides (AMPs) are universal effector molecules that directly eliminate invading pathogenic bacteria, fungi, viruses, and parasites. In mammals, including humans, such peptides may also modulate the adaptive immune systems. To date, more than 1600 AMPs have been identified in bacteria, fungi, plants, and animals. To better manage this information, my laboratory has established the Antimicrobial Peptide database (APD) as a tool for AMP naming, classification, search, statistical analysis, prediction, and design. Our database is also a useful resource for developing novel antimicrobial agents. These miniature proteins are capable of adopting a variety of three-dimensional structures, inspiring our design of natural mimics that benefit mankind. The objective of one of our NIH-funded projects is to develop AMPs into novel anti-HIV microbicides in collaboration with ImQuest BioSciences.
We are particularly interested in an in-depth understanding of the functional roles of human AMPs and their relationships with human diseases, including cancer. Recently, we have solved high-quality structures of human cathelicidin LL-37 and its important fragments by multidimensional nuclear magnetic resonance (NMR) spectroscopy. Dioctanoyl phosphatidylglycerol (D8PG) has been established as a new and unique membrane-mimetic model, which enables the detection of Phe-PG and Arg-PG interactions. Based on three-dimensional structures, we have identified the most potent region within LL-37 against MRSA, thereby identifying a useful template for designing novel therapeutic compounds against this superbug (US Patent 7,465,784). To elucidate the mechanism of action, we are utilizing a variety of biophysical and biochemical techniques. Our studies will lay the foundation for peptide engineering with a goal to overcome the hurdles (stability, toxicity, and production) on the way to the development of natural AMPs into novel therapeutics.
Another research direction of high interest to us is to engineer molecules that control protein-mediated signal transduction pathways essential for bacterial survival or infection in collaboration with colleagues in the Center for Staphylococcal Research (CSR). The lead compound will be optimized by combining NMR-based library screening with rational design based on three-dimensional structures of protein-protein complexes.