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dc.contributor.authorMartinecz, Antal
dc.contributor.authorClarelli, Fabrizio
dc.contributor.authorAbel, Sören
dc.contributor.authorAbel zur Wiesch, Pia
dc.date.accessioned2019-08-20T08:05:17Z
dc.date.available2019-08-20T08:05:17Z
dc.date.issued2019-08-15
dc.description.abstractBacterial 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.en_US
dc.description.sponsorshipBill and Melinda Gates Foundation Helse-Nord UiT—The Arctic University of Norway, the publication funden_US
dc.descriptionSource at <a href=https://doi.org/10.3390/ijms20163965>https://doi.org/10.3390/ijms20163965. </a>en_US
dc.identifier.citationMartinecz, A., Clarelli, F., Abel, S. & Abel zur Wiesch, P. (2019). Reaction Kinetic Models of Antibiotic Heteroresistance. <i>International Journal of Molecular Sciences, 20</i>(16), 3965. https://doi.org/10.3390/ijms20163965en_US
dc.identifier.issn1422-0067
dc.identifier.otherFRIDAID 1716537
dc.identifier.other10.3390/ijms20163965
dc.identifier.urihttps://hdl.handle.net/10037/15963
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.relation.journalInternational Journal of Molecular Sciences
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRIMEDBIO/262686/Norway/Predicting optimal antibiotic treatment regimens//en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRIMEDBIO/249979/Norway/Host defenses against Vibrio cholerae and molecular virulence mechanisms to overcome them//en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.subjectreaction kineticsen_US
dc.subjectantibioticsen_US
dc.subjectpharmacodynamicsen_US
dc.subjectGillespie algorithmen_US
dc.subjectantibiotic resistanceen_US
dc.subjectbacterial persistenceen_US
dc.subjectstochastic simulationen_US
dc.titleReaction Kinetic Models of Antibiotic Heteroresistanceen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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