Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions
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.
- Research Organization:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Organization:
- USDOE Laboratory Directed Research and Development (LDRD) Program
- Grant/Contract Number:
- Laboratory Directed Research and Development; AC52-06NA25396
- OSTI ID:
- 1338427
- Alternate ID(s):
- OSTI ID: 1335619
- Report Number(s):
- LA-UR-15-28626; 10.1371/journal.pone.0165899
- Journal Information:
- PLoS ONE, Journal Name: PLoS ONE Vol. 11 Journal Issue: 11; ISSN 1932-6203
- Publisher:
- Public Library of Science (PLoS)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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