Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions
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.
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1338427
- Alternate Identifier(s):
- OSTI ID: 1335619
- Report Number(s):
- LA-UR-15-28626
Journal ID: ISSN 1932-6203; 10.1371/journal.pone.0165899
- Grant/Contract Number:
- Laboratory Directed Research and Development; AC52-06NA25396
- Resource Type:
- Published Article
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Name: PLoS ONE Journal Volume: 11 Journal Issue: 11; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Biological Science
Citation Formats
Vesselinova, Neda, Alexandrov, Boian S., Wall, Michael E., and Vilar, ed., Jose M. G. Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions. United States: N. p., 2016.
Web. doi:10.1371/journal.pone.0165899.
Vesselinova, Neda, Alexandrov, Boian S., Wall, Michael E., & Vilar, ed., Jose M. G. Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions. United States. https://doi.org/10.1371/journal.pone.0165899
Vesselinova, Neda, Alexandrov, Boian S., Wall, Michael E., and Vilar, ed., Jose M. G. Tue .
"Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions". United States. https://doi.org/10.1371/journal.pone.0165899.
@article{osti_1338427,
title = {Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions},
author = {Vesselinova, Neda and Alexandrov, Boian S. and Wall, Michael E. and Vilar, ed., Jose M. G.},
abstractNote = {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.},
doi = {10.1371/journal.pone.0165899},
journal = {PLoS ONE},
number = 11,
volume = 11,
place = {United States},
year = {Tue Nov 08 00:00:00 EST 2016},
month = {Tue Nov 08 00:00:00 EST 2016}
}
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