title: Correlating Drug-Target Kinetics andIn vivoPharmacodynamics: Long Residence Time Inhibitors of the FabI Enoyl-ACP Reductase.
abstract: 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 predictin vivopharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model ofPseudomonas aeruginosainfection. In the present work we demonstrate that the same approach can be used to predict thein vivoactivity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistantStaphylococcus aureus(MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In additionP. aeruginosais a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Fereidoon
authors.initials: F
authors.lastname: Daryaee
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chang
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, D-97080 Würzburg, Germany; Institute of Pharmacy and Food Chemistry, University of Würzburg, D-97074 Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schiebel
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Kanishk
authors.initials: K
authors.lastname: Kapilashrami
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Oral Biology and Pathology Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Walker
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Würzburg, D-97074 Würzburg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.affiliation: The Broad Institute, Cambridge MA 02142, USA.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Fisher
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge