Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS

Rice, Amy J.; Pesavento, Russell P.; Ren, Jinhong; Youn, Isoo; Kwon, Yong Hwan; Ellepola, Kassapa; Che, Chun‐Tao; Johnson, Michael E.; Lee, Hyun

doi:10.3390/ijms22189984

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…Aquifex aeolicus DHOase (AaDHOase) is active only when complexed with AaATCase [ 5 ]. Given that CAD is a key enzyme for the cell’s progression through the S phase of the cell cycle and controls the cell proliferation in mammalian cells [ 6 , 7 , 8 ], these distinct differences among species may indicate that DHOase is a promising target [ 9 , 10 , 11 ] for potential antimalarial, anticancer, and antipathogen chemotherapy [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Saccharomyces cerevisiae Dihydroorotase Reveals Molecular Insights into the Tetramerization Mechanism

et al. 2021

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Dihydroorotase (DHOase), a dimetalloenzyme containing a carbamylated lysine within the active site, is a member of the cyclic amidohydrolase family, which also includes allantoinase (ALLase), dihydropyrimidinase (DHPase), hydantoinase, and imidase. Unlike most known cyclic amidohydrolases, which are tetrameric, DHOase exists as a monomer or dimer. Here, we report and analyze two crystal structures of the eukaryotic Saccharomyces cerevisiae DHOase (ScDHOase) complexed with malate. The structures of different DHOases were also compared. An asymmetric unit of these crystals contained four crystallographically independent ScDHOase monomers. ScDHOase shares structural similarity with Escherichia coli DHOase (EcDHOase). Unlike EcDHOase, ScDHOase can form tetramers, both in the crystalline state and in solution. In addition, the subunit-interacting residues of ScDHOase for dimerization and tetramerization are significantly different from those of other DHOases. The tetramerization pattern of ScDHOase is also different from those of DHPase and ALLase. Based on sequence analysis and structural evidence, we identify two unique helices (α6 and α10) and a loop (loop 7) for tetramerization, and discuss why the residues for tetramerization in ScDHOase are not necessarily conserved among DHOases.

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Section: Introductionmentioning

confidence: 99%

Structural Analysis of Saccharomyces cerevisiae Dihydroorotase Reveals Molecular Insights into the Tetramerization Mechanism

et al. 2021

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“…coli [ 48 ], the HIV-1 integrase strand transfer complex [ 49 ], dihydroorotase in S . aureus [ 50 ], and most recently there has been a significant effort to target the main protease (M pro ) of SARS-CoV-2 [ 51 – 53 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the BspC-vimentin interaction to develop anti-virulence therapies during Group B streptococcal meningitis

2022

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Bacterial infections are a major cause of morbidity and mortality worldwide and the rise of antibiotic resistance necessitates development of alternative treatments. Pathogen adhesins that bind to host cells initiate disease pathogenesis and represent potential therapeutic targets. We have shown previously that the BspC adhesin in Group B Streptococcus (GBS), the leading cause of bacterial neonatal meningitis, interacts with host vimentin to promote attachment to brain endothelium and disease development. Here we determined that the BspC variable (V-) domain contains the vimentin binding site and promotes GBS adherence to brain endothelium. Site directed mutagenesis identified a binding pocket necessary for GBS host cell interaction and development of meningitis. Using a virtual structure-based drug screen we identified compounds that targeted the V-domain binding pocket, which blocked GBS adherence and entry into the brain in vivo. These data indicate the utility of targeting the pathogen-host interface to develop anti-virulence therapeutics.

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“…In this study, we identified that S. purpurea-root-acetone could inhibit the enzymatic activity of huDHOase. DHOase is the third enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides (Figure 7A) and is considered an attractive target for potential antimalarial, anticancer, and antipathogen chemotherapy [17,[39][40][41]43,[54][55][56][57][58][59][60][61]. This enzyme contains a binuclear metal center (Znα/Znβ) and a residue Asp1686 (Figure 7B) crucial for the catalysis [42,[62][63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Anticancer and Antioxidant Activities of the Root Extract of the Carnivorous Pitcher Plant Sarracenia purpurea

Huang

Chiang

Chen

et al. 2022

Plants

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The carnivorous pitcher plant Sarracenia purpurea exhibits many ethnobotanical uses, including the treatments of type 2 diabetes and tuberculosis-like symptoms. In this study, we prepared different extracts from the leaves (pitchers), stems, and roots of S. purpurea and investigated their antioxidant and anticancer properties. To evaluate the extraction efficiency, we individually used different solvents, namely methanol, ethanol, acetone, and distilled water, for S. purpurea extract preparations. The root extract of S. purpurea, obtained by 100% acetone (S. purpurea-root-acetone), had the highest anticancer activities, antioxidation capacity (the DPPH activity with IC50 of 89.3 ± 2.2 μg/mL), antibacterial activities, total phenolic content (33.4 ± 0.7 mg GAE/g), and total flavonoid content (107.9 ± 2.2 mg QUE/g). The most abundant compounds in S. purpurea-root-acetone were identified using gas chromatography–mass spectrometry; 7,8-Dihydro-α-ionone was the major compound present in S. purpurea-root-acetone. In addition, the co-cytotoxicity of S. purpurea-root-acetone (combined with the clinical anticancer drug 5-fluorouracil (5-FU) on the survival, apoptosis, proliferation, and migration of the 4T1 mammary carcinoma) was examined. The combination of 5-FU with S. purpurea-root-acetone could be highly efficient for anti-4T1 cells. We also found that S. purpurea-root-acetone could inhibit the enzymatic activity of human dihydroorotase (huDHOase), an attractive target for potential anticancer chemotherapy. The sic most abundant compounds in S. purpurea-root-acetone were tested using an in silico analysis via MOE-Dock software for their binding affinities. The top-ranked docking conformations were observed for 7,8-dihydro-α-ionone and stigmast-5-en-3-ol, suggesting the inhibition potential against huDHOase. Overall, the collective data in this study may indicate the pharmacological potentials of S. purpurea-root-acetone for possible medical applications.

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Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS

Cited by 6 publications

References 16 publications

Structural Analysis of Saccharomyces cerevisiae Dihydroorotase Reveals Molecular Insights into the Tetramerization Mechanism

Structural Analysis of Saccharomyces cerevisiae Dihydroorotase Reveals Molecular Insights into the Tetramerization Mechanism

Targeting the BspC-vimentin interaction to develop anti-virulence therapies during Group B streptococcal meningitis

Anticancer and Antioxidant Activities of the Root Extract of the Carnivorous Pitcher Plant Sarracenia purpurea

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