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Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus

Johnson, Paul J T ; Levin, Bruce R Malik, Harmit S.

PLoS genetics, 2013-01, Vol.9 (1), p.e1003123 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus
Autor: Johnson, Paul J T ; Levin, Bruce R
Malik, Harmit S.
Assuntos: Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Antibiotics ; Bacteria ; Bacterial genetics ; Bacterial infections ; Biological Evolution ; Biology ; Drug Resistance, Bacterial - genetics ; Experiments ; Genetic aspects ; Health aspects ; Humans ; Hypotheses ; Mathematical models ; Medical research ; Medicine ; Models, Theoretical ; Mutation ; Pharmacogenetics ; Physiological aspects ; Population ; Population Dynamics ; Population genetics ; Selection, Genetic ; Staphylococcal Infections - genetics ; Staphylococcus aureus ; Staphylococcus aureus - drug effects ; Staphylococcus aureus - genetics ; Staphylococcus aureus - pathogenicity
É parte de: PLoS genetics, 2013-01, Vol.9 (1), p.e1003123
Notas: Conceived and designed the experiments: PJTJ BRL. Performed the experiments: PJTJ BRL. Analyzed the data: PJTJ BRL. Contributed reagents/materials/analysis tools: PJTJ BRL. Wrote the paper: PJTJ BRL.
The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus

Johnson, Paul J T ; Levin, Bruce R Malik, Harmit S.

United States: Public Library of Science

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