Mechanics of membrane targeting antimicrobials - Pore nucleation in bacterial membranes

The lipid bilayer membrane is increasingly recognized as a promising target for medicine, as exemplified by the recent surge in the development of membrane targeting antimicrobials (MTAs) against methicillin-resistant Staphylococcus aureus (MRSA), a superbug posing significant challenges to public health. Interestingly, the effectiveness of MTAs seems to vary markedly between the exponential growth and stationary phases of bacteria, a phenomenon that remains poorly understood. Here, we perform molecular dynamics (MD) simulations of the lipid bilayer membrane of S. aureus across different phases of bacteria growth, examining equilibrium properties and free energies associated with pore nucleation, the initial stage of membrane perforation preceding pore expansion and rupture. Our findings reveal that pore nucleation in the stationary phase bacterial membrane requires more energy compared to the exponential phase due to the increased concentration of cardiolipin, a type of mechanically resilient lipids, in the former, which provides a physical explanation for why the stationary phase is more tolerant of MTAs. The insights gained from this study not only deepen our understanding of the mechanics of bacterial membrane but can also help lay a foundation for simulation-assisted discovery and evaluation of MTAs for optimized treatments.