Issue 9, 2016

Correlating drug–target kinetics and in vivo pharmacodynamics: 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 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.

Graphical abstract: Correlating drug–target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase

Supplementary files

Article information

Article type
Edge Article
Submitted
03 Mar 2016
Accepted
20 May 2016
First published
25 May 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2016,7, 5945-5954

Correlating drug–target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase

F. Daryaee, A. Chang, J. Schiebel, Y. Lu, Z. Zhang, K. Kapilashrami, S. G. Walker, C. Kisker, C. A. Sotriffer, S. L. Fisher and P. J. Tonge, Chem. Sci., 2016, 7, 5945 DOI: 10.1039/C6SC01000H

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