1. Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product
- Author
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David Smil, Masoud Vedadi, Hee-Won Park, Abdellah Allali-Hassani, Erick Strauss, Tetyana Antoshchenko, Scott J. Hughes, Katayoun Mottaghi, Leanne Barnard, Bum Soo Hong, and Wolfram Tempel
- Subjects
Models, Molecular ,0301 basic medicine ,Staphylococcus aureus ,Stereochemistry ,Coenzyme A ,030106 microbiology ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,Catalytic Domain ,medicine ,Structure–activity relationship ,Enzyme kinetics ,Enzyme Inhibitors ,Phosphorylation ,chemistry.chemical_classification ,biology ,Active site ,Staphylococcal Infections ,3. Good health ,Kinetics ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Infectious Diseases ,Enzyme ,chemistry ,Mechanism of action ,Biochemistry ,biology.protein ,Pantothenate kinase ,Growth inhibition ,medicine.symptom - Abstract
The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus’s atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm. The cocrystal structures showed that all of the PanAms are phosphorylated by SaPanKII but remain bound at the active site; this occurs primarily through interactions with Tyr240′ and Thr172′. Kinetic analysis showed a strong correlation between kcat (slow PanAm turnover) and IC50 (inhibition of pantothenate phosphorylation) va...
- Published
- 2016
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