Interplay between Population Dynamics and Drug Tolerance of <b><i>Staphylococcus aureus</i></b> Persister Cells

Population dynamics parameters of Staphylococcus aureus strain SA113 were quantified based on growth and killing experiments with batch culture cells in rich medium. Eradication kinetics and the concomitant isolation of a subpopulation of drug-tolerant SA113 persisters upon treatment with super-minimal inhibitory concentrations of antibiotics such as ciprofloxacin, daptomycin, and tobramycin served as a basis for mathematical analyses. According to a two-state model for stochastic phenotype switching, levels of persister cells and their eradication rates were influenced by the antibiotics used for isolation, clearly indicating a heterogeneous pool of S. aureus persisters. Judging from time-dependent experiments, the persisters' degree of drug tolerance correlated with the duration of antibiotic challenge. Moreover, cross-tolerance experiments with cells consecutively treated with two different antibiotics revealed that multi-drug tolerance is not a necessary trait of S. aureus persisters isolated by antibiotic challenge. In some cases, the results depended on the order of the two antibiotic treatments, suggesting that antibiotic tolerance may be achieved by a combination of preexisting persisters and an adaptive response to drug exposure. Counts of live cells which had endured drug treatment increased only after lag phases of at least 3 h after the shift to non-selective conditions. Thus, this study provides quantitative insights into population dynamics of S. aureus persisters with regard to antibiotic challenge.