TY  - JOUR
A1  - Daryaee, Fereidoon
A1  - Chang, Andrew
A1  - Schiebel, Johannes
A1  - Lu, Yang
A1  - Zhang, Zhuo
A1  - Kapilashrami, Kanishk
A1  - Walker, Stephen G.
A1  - Kisker, Caroline
A1  - Sotriffer, Christoph A.
A1  - Fisher, Stewart L.
A1  - Tonge, Peter J.
T1  - Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase
JF  - Chemical Science
N2  - 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.
KW  - Staphylococcus aureus
KW  - antibacterial activity
KW  - LpxC inhibitors
KW  - enoyl-ACP reductase inhibitors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191218
VL  - 7
IS  - 9
ER  -