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Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS

1
Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
3
Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60607, USA
4
Biophysics Core at the Research Resource Center, University of Illinois at Chicago, Chicago, IL 60607, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Sotiris K. Hadjikakou
Int. J. Mol. Sci. 2021, 22(18), 9984; https://doi.org/10.3390/ijms22189984
Received: 16 August 2021 / Revised: 2 September 2021 / Accepted: 11 September 2021 / Published: 15 September 2021
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: S. aureus; antimicrobial; dihydroorotase; Class I DHOase; inhibitors S. aureus; antimicrobial; dihydroorotase; Class I DHOase; inhibitors
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MDPI and ACS Style

Rice, A.J.; Pesavento, R.P.; Ren, J.; Youn, I.; Kwon, Y.; Ellepola, K.; Che, C.-T.; Johnson, M.E.; Lee, H. Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS. Int. J. Mol. Sci. 2021, 22, 9984. https://doi.org/10.3390/ijms22189984

AMA Style

Rice AJ, Pesavento RP, Ren J, Youn I, Kwon Y, Ellepola K, Che C-T, Johnson ME, Lee H. Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS. International Journal of Molecular Sciences. 2021; 22(18):9984. https://doi.org/10.3390/ijms22189984

Chicago/Turabian Style

Rice, Amy J., Russell P. Pesavento, Jinhong Ren, Isoo Youn, Youngjin Kwon, Kassapa Ellepola, Chun-Tao Che, Michael E. Johnson, and Hyun Lee. 2021. "Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS" International Journal of Molecular Sciences 22, no. 18: 9984. https://doi.org/10.3390/ijms22189984

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