Antimicrobial peptides (AMPs) are ancient and conserved across the tree of life. They are the most important components in immune system due to their distinct mechanisms of killing bacteria. In this thesis, a pharmacodynamic approach was taken to investigate why bacteria are less likely to develop resistance to the nature immune system, especially to one of its components AMPs. In this thesis, the combination effects of AMPs were firstly investigated. Six different AMPs from different organisms

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... were selected to test their individual and combined effects in vitro. With an approach based on pharmacodynamics and Loewe additivity, the interactions of AMPs were found mostly synergistic. Three-AMP combinations displayed stronger synergism than two-AMP combinations. Additionally, AMPs displayed a sharp increase in killing within a narrow dose range contrasting with those of antibiotics. Followed by a theoretical study, the combination effect between AMPs was explored using mathematical model that captures the dynamics of attachment and detachment between AMPs and cell membrane. In this multi-hit model, bacteria are killed when a certain number of targets are hit by antimicrobials. This bottom-up approach revealed that Bliss independence should be the model of choice if no interaction between antimicrobial molecules is expected; Loewe additivity, on the other hand, describes scenarios in which antimicrobials affect the same components of the cell, i.e. are not acting independently. The choice of the additivity term is essential to determine synergy or antagonism of antimicrobials. The AMPs were found fundamentally different from antibiotics in their pharmacodynamic characteristics. This difference was further implemented within a theoretical framework to predict the evolution of resistance. The comparative analysis of resistance evolution demonstrated that pharmacodynamic differences all combine to produce a much lower probability that resistance will evolve against antimicrobial peptides. The finding can be generalized [...]