(375f) Modeling the Action of Antimicrobial Peptides: Transient Diffusion of Ions and Osmotically-Driven Flow

Antimicrobial peptides (AMPs) are a promising new class of antibiotics that are believed to kill pathogens by permealizing their cell membranes. The present work focuses on protegrin, a particularly effective AMP derived from porcine leukocytes, believed to act primarily by forming octameric transmembrane pores. We present herein a combined modeling and experimental effort aimed at elucidating the mechanism of action of this peptide. We have modeled steady-state electrodiffusion of ions through a protegrin pore based on a continuum theory (Poisson-Nernst-Planck theory). Good agreement was obtained with previous experimental conductance measurements. We have then used the results of this model as input to a larger scale model that analyzes the time-dependent transport of ions from the cell, the decay of the transmembrane potential, and the volume changes associated with osmotic flow across the membrane. Comparison with experimental data at this level allows us to estimate the effective number of pores at 10-100, depending on the bacterial growth stage. We can also surmise that ion exchange processes alone are likely not solely responsible for the experimentally observed cell swelling and osmotic lysing. Given the measured kinetics of bacterial viability loss, bacterial death appears to be largely a result of uncontrolled ion exchange processes and transmembrane potential decay, while osmotic lysing constitutes a redundant overkill mechanism. The tools presented herein represent a multi-faceted, multiscale analysis applicable to similar AMP systems, and membrane transport processes in general.