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Open AccessArticle

Reaction Kinetic Models of Antibiotic Heteroresistance

Department of Pharmacy, Faculty of Health Sciences, UiT—The Arctic University of Norway, 9037 Tromsø, Norway
Centre for Molecular Medicine Norway, P.O. Box 1137, Blindern, 0318 Oslo, Norway
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3965;
Received: 12 July 2019 / Revised: 12 August 2019 / Accepted: 13 August 2019 / Published: 15 August 2019
(This article belongs to the Special Issue Solution Chemical Kinetics 2019)
Bacterial heteroresistance (i.e., the co-existence of several subpopulations with different antibiotic susceptibilities) can delay the clearance of bacteria even with long antibiotic exposure. Some proposed mechanisms have been successfully described with mathematical models of drug-target binding where the mechanism’s downstream of drug-target binding are not explicitly modeled and subsumed in an empirical function, connecting target occupancy to antibiotic action. However, with current approaches it is difficult to model mechanisms that involve multi-step reactions that lead to bacterial killing. Here, we have a dual aim: first, to establish pharmacodynamic models that include multi-step reaction pathways, and second, to model heteroresistance and investigate which molecular heterogeneities can lead to delayed bacterial killing. We show that simulations based on Gillespie algorithms, which have been employed to model reaction kinetics for decades, can be useful tools to model antibiotic action via multi-step reactions. We highlight the strengths and weaknesses of current models and Gillespie simulations. Finally, we show that in our models, slight normally distributed variances in the rates of any event leading to bacterial death can (depending on parameter choices) lead to delayed bacterial killing (i.e., heteroresistance). This means that a slowly declining residual bacterial population due to heteroresistance is most likely the default scenario and should be taken into account when planning treatment length. View Full-Text
Keywords: reaction kinetics; antibiotics; pharmacodynamics; Gillespie algorithm; antibiotic resistance; bacterial persistence; stochastic simulation reaction kinetics; antibiotics; pharmacodynamics; Gillespie algorithm; antibiotic resistance; bacterial persistence; stochastic simulation
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Martinecz, A.; Clarelli, F.; Abel, S.; Abel zur Wiesch, P. Reaction Kinetic Models of Antibiotic Heteroresistance. Int. J. Mol. Sci. 2019, 20, 3965.

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