Unraveling the Membrane-Selective Mechanism of Lugdunin: Insights into Specificity for Gram-Positive Bacteria and Antimicrobial Activity

• Applicants: Professor Dr. Rainer Böckmann; Professorin Dr. Claudia Steinem
• Subject Area: Biophysics ; Biological and Biomimetic Chemistry ; Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555589280

The cyclic heptapeptide lugdunin, produced by Staphylococcus lugdunensis, has significant activity against multidrug-resistant Gram-positive bacteria but is ineffective against Gram-negative bacteria and human cells. Previous studies suggest that lugdunin disrupts the membrane potential of pathogens such as S. aureus by making the membranes permeable to protons without forming large pores, leading to cell death. However, the exact molecular mechanism remains still unclear. In this project, we aim to comprehensively characterize the membrane-selective mechanism of lugdunin. We hypothesize that the specificity of lugdunin for Gram-positive bacterial membranes is determined by their unique lipid composition, which facilitates lugdunin insertion, channel formation and activity. The project will investigate the interactions between lugdunin and model membranes that mimic Gram-positive and Gram-negative bacterial membranes as well as eukaryotic cell membranes. This will be achieved by complementary in vitro and in silico analyses of artificial membrane systems and synthetic lugdunin analogs. By analyzing the molecular interactions involved, we aim to uncover the determinants of lugdunin's membrane selectivity, ion transport properties, and key structural factors influencing its antimicrobial activity. The expected findings will feed into the development of next-generation antimicrobial peptides that may offer new therapeutic strategies against resistant bacterial infections.

• DFG Programme: Research Grants