PT  - JOURNAL ARTICLE
AU  - Neda Vesselinova
AU  - Boian S. Alexandrov
AU  - Michael E. Wall
TI  - Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions
AID  - 10.1101/030908
DP  - 2015 Jan 01
TA  - bioRxiv
PG  - 030908
4099  - http://biorxiv.org/content/early/2015/11/07/030908.short
4100  - http://biorxiv.org/content/early/2015/11/07/030908.full
AB  - We present a dynamical model of drug accumulation in bacteria. The model captures key features in experimental time courses on ofloxacin accumulation: initial uptake; short-term response; and long-term adaptation. In combination with experimental data, the model provides estimates of import and export rates in each phase, the latency in the short-term response, and the rate of increase in efflux during adaptation. 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 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 membrane permeability and drug efflux and trapping, which influence drug resistance. A key prediction is that an increase in E. coli ofloxacin accumulation is accompanied by a decrease in membrane permeability, suggesting that, depending on changes in other factors, decreasing permeability is not always an effective drug resistance strategy.Author Summary. Bacteria live or die depending on how much antibiotic gets inside them. Using a simple mathematical model, detailed information about drug import and export can be teased out of time courses of internal drug levels after a sudden environmental exposure. The results reveal that blocking diffusion across the membrane is not always an effective drug resistance strategy for bacteria.