Resistance Evolution Against Antimicrobial Peptides in Staphylococcus aureus Alters Pharmacodynamics Beyond the MIC

Antimicrobial peptides (AMPs) have been proposed as a promising class of new antimicrobials partly because they are less susceptible to bacterial resistance evolution. This is possibly caused by their mode of action but also by their pharmacodynamic characteristics, which differ significantly from conventional antibiotics. Although pharmacodynamics of antibiotic resistant strains have been studied, such data are lacking for AMP resistant strains. Here, we investigated if the pharmacodynamics of the Gram-positive human pathogen evolve under antimicrobial peptide selection. Interestingly, the Hill coefficient (kappa κ) evolves together with the minimum inhibition concentration (MIC). Except for one genotype, strains harboring mutations in F and , all mutants had higher kappa than the non-selected sensitive controls. Higher κ results in steeper pharmacodynamic curve and, importantly, in a narrower mutant selection window. selected for resistance to melittin displayed cross resistant against pexiganan and had as steep pharmacodynamic curves (high κ) as pexiganan-selected lines. By contrast, the pexiganan-sensitive tenecin-selected lines displayed lower κ. Taken together, our data demonstrate that pharmacodynamic parameters are not fixed traits of particular drug/strain interactions but actually evolve under drug treatment. The contribution of factors such as κ and the maximum and minimum growth rates on the dynamics and probability of resistance evolution are open questions that require urgent attention.