Dataset Information

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

ABSTRACT: 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 Staphylococcous aureus evolve under antimicrobial peptide selection. Interestingly, the Hill coefficient (kappa ?) evolves together with the minimum inhibition concentration (MIC). Except for one genotype, strains harboring mutations in menF and atl, all mutants had higher kappa than the non-selected sensitive controls. Higher ? results in steeper pharmacodynamic curve and, importantly, in a narrower mutant selection window. S. aureus selected for resistance to melittin displayed cross resistant against pexiganan and had as steep pharmacodynamic curves (high ?) as pexiganan-selected lines. By contrast, the pexiganan-sensitive tenecin-selected lines displayed lower ?. 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 ? and the maximum and minimum growth rates on the dynamics and probability of resistance evolution are open questions that require urgent attention.

SUBMITTER: El Shazely B

PROVIDER: S-EPMC7033599 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Resistance Evolution Against Antimicrobial Peptides in <i>Staphylococcus aureus</i> Alters Pharmacodynamics Beyond the MIC.

El Shazely Baydaa B Yu Guozhi G Johnston Paul R PR Rolff Jens J

Frontiers in microbiology 20200214

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 ...[more]

PMID: 32117132

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Project description:When growing populations of bacteria are confronted with bactericidal antibiotics, the vast majority of cells are killed, but subpopulations of genetically susceptible but phenotypically resistant bacteria survive. In accord with the prevailing view, these "persisters" are non- or slowly dividing cells randomly generated from the dominant population. Antibiotics enrich populations for pre-existing persisters but play no role in their generation. The results of recent studies with Escherichia coli suggest that at least one antibiotic, ciprofloxacin, can contribute to the generation of persisters. To more generally elucidate the role of antibiotics in the generation of and selection for persisters and the nature of persistence in general, we use mathematical models and experiments with Staphylococcus aureus (Newman) and the antibiotics ciprofloxacin, gentamicin, vancomycin, and oxacillin. Our results indicate that the level of persistence varies among these drugs and their concentrations, and there is considerable variation in this level among independent cultures and mixtures of independent cultures. A model that assumes that the rate of production of persisters is low and persisters grow slowly in the presence of antibiotics can account for these observations. As predicted by this model, pre-treatment with sub-MIC concentrations of antibiotics substantially increases the level of persistence to drugs other than those with which the population is pre-treated. Collectively, the results of this jointly theoretical and experimental study along with other observations support the hypothesis that persistence is the product of many different kinds of errors in cell replication that result in transient periods of non-replication and/or slowed metabolism by individual cells in growing populations. This Persistence as Stuff Happens (PaSH) hypothesis can account for the ubiquity of this phenomenon. Like mutation, persistence is inevitable rather than an evolved character. What evolved and have been identified are genes and processes that affect the frequency of persisters.

Dataset Information

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

Publications

Resistance Evolution Against Antimicrobial Peptides in <i>Staphylococcus aureus</i> Alters Pharmacodynamics Beyond the MIC.

Similar Datasets

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