Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-191218
- 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 in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACPDrug-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 in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.…
Autor(en): | Fereidoon Daryaee, Andrew Chang, Johannes Schiebel, Yang Lu, Zhuo Zhang, Kanishk Kapilashrami, Stephen G. Walker, Caroline Kisker, Christoph A. Sotriffer, Stewart L. Fisher, Peter J. Tonge |
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URN: | urn:nbn:de:bvb:20-opus-191218 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Biologie / Rudolf-Virchow-Zentrum |
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Chemical Science |
Erscheinungsjahr: | 2016 |
Band / Jahrgang: | 7 |
Heft / Ausgabe: | 9 |
Seitenangabe: | 5945-5954 |
Originalveröffentlichung / Quelle: | Chemical Science (2016) 7:9, S. 5945-5954. https://doi.org/10.1039/c6sc01000h |
DOI: | https://doi.org/10.1039/c6sc01000h |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie | |
Freie Schlagwort(e): | LpxC inhibitors; Staphylococcus aureus; antibacterial activity; enoyl-ACP reductase inhibitors |
Datum der Freischaltung: | 15.02.2021 |
Lizenz (Deutsch): | CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell |