Correlating Drug-Target Kinetics and In vivo Pharmacodynamics: Long Residence Time Inhibitors of the FabI Enoyl-ACP Reductase

Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that suc...

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Published inChemical science (Cambridge) Vol. 7; no. 9; pp. 5945 - 5954
Main Authors Daryaee, Fereidoon, Chang, Andrew, Schiebel, Johannes, Lu, Yang, Zhang, Zhuo, Kapilashrami, Kanishk, Walker, Stephen G, Kisker, Caroline, Sotriffer, Christoph A, Fisher, Stewart L, Tonge, Peter J
Format Journal Article
LanguageEnglish
Published England 01.01.2016
Subjects
Antiinfectives and antibacterials
Drugs
Inhibitors
Mathematical models
MRSA
Pharmacology
Reductases
Staphylococcus aureus
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Summary:Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of infection. In the present work we demonstrate that the same approach can be used to predict the activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.
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ISSN:2041-6520
2041-6539
DOI:10.1039/c6sc01000h