Abstract
We present a dynamical model of drug accumulation in bacteria. The model captures key features in experimental time courses on ofloxacin accumulation: initial uptake; two-phase response; and long-term acclimation. In combination with experimental data, the model provides estimates of import and export rates in each phase, the time of entry into the second phase, and the decrease of internal drug during acclimation. Global sensitivity analysis, local sensitivity analysis, and Bayesian sensitivity analysis of the model provide information about the robustness of these estimates, and about the relative importance of different parameters in determining the features of the accumulation time courses in three different bacterial species: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results lead to experimentally testable predictions of the effects of membrane permeability, drug efflux and trapping (e.g., by DNA binding) on drug accumulation. A key prediction is that a sudden increase in ofloxacin accumulation in both E. coli and S. aureus is accompanied by a decrease in membrane permeability.
Highlights
Drug resistance in bacteria can be increased by efflux pump systems [1], and pump inhibition has emerged as a strategy for overcoming drug resistance [2]
The present modeling and analysis of ofloxacin accumulation time courses indicates that E. coli and S. aureus exhibit a similar two-phase ofloxacin accumulation behavior
Whereas the twophase behavior for E. coli was visible in the data, for S. aureus it was only detected as a result of the Bayesian sensitivity analysis (BSA)
Summary
Drug resistance in bacteria can be increased by efflux pump systems [1], and pump inhibition has emerged as a strategy for overcoming drug resistance [2]. Many details of how efflux pumps work are still unclear, . Quantitative information about how efflux influences drug accumulation in bacteria is still scarce [3]. Drug accumulation is a key factor in obtaining a quantitative understanding of resistance. Predictions of minimum inhibitory concentrations (MICs) of β-lactams in Escherichia coli were obtained by equating the steady state periplasmic drug concentration with a periplasmic binding protein inhibitory concentration [4]. A predicted MIC was calculated as the external concentration that would yield the accumulated internal inhibitory concentration in steady state, considering flux terms from membrane permeation and β-lactamase
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