Comparative Study on Human Beta Defensin Type 2 and 3 Interaction with Model Bacterial Lipid Membranes

Natural antimicrobial peptides (AMPs) are considered the solution to infectious diseases and the antibiotic inefficiency caused by bacterial resistance. Among natural AMPs, human beta defensin type 3 (hBD-3) is unique that it has a broader spectrum of and stronger antimicrobial activities against both Gram-positive and Gram-negative bacteria than other hBDs. It is believed that hBD-3 kills bacteria by directly disrupting bacterial lipid membranes, although its functional mechanism in molecular detail is unclear yet. However, the functional mechanism of human beta defensin type 2 (hBD-2) is known, which has a very similar secondary structure to hBD-3. To design novel drugs based on hBD-3, it is important to find out its functional mechanism. To fill this knowledge gap, we propose to conduct a comparative study investigating the binding structures of hBD-2 and hBD-3 with different explicit model bacterial lipid membranes using both solid-state NMR and molecular dynamics simulation methods, and evaluate the biological activity of hBDs through activity assays. The hypothesis is that the binding structure of hBD with lipids and its interaction with key molecules in the membranes determine its antibacterial mechanism. This project will help uncover the mysteries associated with hBD-3 disrupting bacterial cell membranes. Our methods applied will also pave the way for researching the mechanisms of other AMPs that disrupt bacterial lipid membranes. Project Number: 1R15GM163254-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Liqun Zhang | Institution: UNIVERSITY OF RHODE ISLAND, KINGSTON, RI | Award Amount: $597,254 | Activity Code: R15 | Study Section: Biochemistry and Biophysics of Membranes Study Section[BBM] View on NIH RePORTER: https://reporter.nih.gov/project-details/11292271