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RSS FeedsIJMS, Vol. 22, Pages 9984: Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS (International Journal of Molecular Sciences)

 
 

15 september 2021 16:18:55

 
IJMS, Vol. 22, Pages 9984: Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS (International Journal of Molecular Sciences)
 


Drug-resistant Staphylococcus aureus is an imminent threat to public health, increasing the importance of drug discovery utilizing unexplored bacterial pathways and enzyme targets. De novo pyrimidine biosynthesis is a specialized, highly conserved pathway implicated in both the survival and virulence of several clinically relevant pathogens. Class I dihydroorotase (DHOase) is a separate and distinct enzyme present in gram positive bacteria (i.e., S. aureus, B. anthracis) that converts carbamoyl-aspartate (Ca-asp) to dihydroorotate (DHO)—an integral step in the de novo pyrimidine biosynthesis pathway. This study sets forth a high-throughput screening (HTS) of 3000 fragment compounds by a colorimetry-based enzymatic assay as a primary screen, identifying small molecule inhibitors of S. aureus DHOase (SaDHOase), followed by hit validation with a direct binding analysis using surface plasmon resonance (SPR). Competition SPR studies of six hit compounds and eight additional analogs with the substrate Ca-asp determined the best compound to be a competitive inhibitor with a KD value of 11 µM, which is 10-fold tighter than Ca-asp. Preliminary structure–activity relationship (SAR) provides the foundation for further structure-based antimicrobial inhibitor design against S. aureus.


 
182 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
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