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.
CITATION STYLE
Daryaee, F., Chang, A., Schiebel, J., Lu, Y., Zhang, Z., Kapilashrami, K., … Tonge, P. J. (2016). Correlating drug-target kinetics and: In vivo pharmacodynamics: Long residence time inhibitors of the FabI enoyl-ACP reductase. Chemical Science, 7(9), 5945–5954. https://doi.org/10.1039/c6sc01000h
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