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Reaction Kinetic Models of Antibiotic Heteroresistance
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 20, Iss 16, p 3965 (2019), Volume 20, Issue 16
- Publication Year :
- 2019
- Publisher :
- MDPI, 2019.
-
Abstract
- 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&rsquo<br />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.
- Subjects :
- 0301 basic medicine
antibiotic resistance
medicine.drug_class
Computer science
030106 microbiology
Antibiotic susceptibilities
Bacterial killing
Antibiotics
bacterial persistence
Microbial Sensitivity Tests
Catalysis
Article
antibiotics
Inorganic Chemistry
lcsh:Chemistry
03 medical and health sciences
Stochastic simulation
Drug Resistance, Bacterial
medicine
pharmacodynamics
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Mathematical model
Mechanism (biology)
Organic Chemistry
Antibiotic exposure
Gillespie algorithm
VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710
General Medicine
VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710
stochastic simulation
Computer Science Applications
Anti-Bacterial Agents
Kinetics
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
reaction kinetics
Biological system
Algorithms
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....6c1b160b097c56a3e32c9dc4aa8e166e