Modeling Cell Selectivity of Antimicrobial Peptides: How Is the Selectivity Influenced by Intracellular Peptide Uptake and Cell Density

Antimicrobial peptides (AMPs) are known to attack bacteria selectively over their host cells. Many attempts have been made to use them as a template for designing peptide antibiotics for fighting drug-resistant bacteria. A central concept in this endeavor is “peptide selectivity,” which measures the “quality” of peptides. However, the relevance of selectivity measurements has often been obscured by the cell-density dependence of the selectivity. For instance, the selectivity can be overestimated if the cell density is larger for the host cell. Furthermore, recent experimental studies suggest that peptide trapping in target bacteria magnifies the cell-density dependence of peptide activity. Here, we propose a biophysical model for peptide activity and selectivity, which assists with the correct interpretation of selectivity measurements. The resulting model shows how cell density and peptide trapping in cells influence peptide activity and selectivity: while these effects can alter the selectivity by more than an order of magnitude, peptide trapping works in favor of host cells at high host-cell densities. It can be used to correct selectivity overestimates.