Abstract
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.
Highlights
While it is convenient to consider genetically identical populations of bacteria as collections of physiologically homogeneous cells, they are commonly composed of phenotypically different subpopulations
In accord with the prevailing view, persisters are non- or slowlygrowing cells generated at random from a dominant population of antibiotic susceptible bacteria
Bactericidal antibiotics reveal the presence of these already existing genetically susceptible but phenotypically resistant subpopulations, but play no role in their generation and ascent. This perspective on the role of antibiotics in the generation and ascent of persisters was recently challenged by Dorr and colleague’s demonstration that preexposure of E. coli to sub-minimum inhibitory concentration (MIC) concentrations of the fluoroquinolone ciprofloxacin increases the frequency of persisters in cultures subsequently exposed to bactericidal concentrations of this drug [29]
Summary
While it is convenient to consider genetically identical populations of bacteria as collections of physiologically homogeneous cells, they are commonly composed of phenotypically different subpopulations. As first reported by John Bigger [7], when growing populations of bacteria are confronted with bactericidal antibiotics, the majority of cells are killed but a minority survive. Upon reculture, these surviving bacteria are as sensitive to antibiotics as the cells from whence they were derived. When exposed to bactericidal antibiotics, they too produced minority populations of survivors. Bigger called these phenotypically resistant but genetically susceptible subpopulations of bacteria ‘‘persisters’’
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