Comparative study on human beta defensin type 2 and 3 interaction with model bacterial lipid membranes

The National Institute of General Medical Sciences awarded the University of Rhode Island $597,254 on May 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to conduct a comparative study on human beta defensin type 2 and type 3 interaction with model bacterial lipid membranes.

The research investigates the binding structures and antimicrobial mechanisms of human beta defensins (HBD-2 and HBD-3) against gram-positive and gram-negative bacteria. The study applies solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulation to examine how these peptides interact with explicit model bacterial lipid membranes, and includes biological activity assays to evaluate antimicrobial efficacy. The work aims to clarify HBD-3's mechanism of bacterial cell membrane disruption, which remains poorly understood despite its broader spectrum and stronger antimicrobial activity compared to other human beta defensins. Findings are intended to inform the design of novel antimicrobial drugs and establish methodologies applicable to research on other antimicrobial peptides that disrupt bacterial lipid membranes.

Performance occurs in Kingston, Rhode Island. The award period runs from May 1, 2026, through April 30, 2029. The University of Rhode Island, a 1862 land-grant public research university operating through its Research Office division, serves as the prime recipient. The State of Rhode Island is the parent organization.

Abstract

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.