Identification of novel inhibitors of phospho-MurNAc-pentapeptide translocase MraY from library screening: Isoquinoline alkaloid michellamine B and xanthene dye phloxine B
| Autor: | Justinas Slikas, Agnes Mihalyi, Timothy D. H. Bugg, Shirin Jamshidi |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Eosine I Bluish
Stereochemistry Clinical Biochemistry Transferases (Other Substituted Phosphate Groups) Pharmaceutical Science Microbial Sensitivity Tests Bacillus subtilis Naphthalenes medicine.disease_cause Biochemistry Pentapeptide repeat Cofactor Small Molecule Libraries Structure-Activity Relationship Bacterial Proteins Transferases Drug Discovery Escherichia coli medicine Translocase Enzyme Inhibitors Molecular Biology Aquifex aeolicus Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Active site Isoquinolines biology.organism_classification Anti-Bacterial Agents biology.protein Molecular Medicine Michellamine B |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:4566-4571 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2014.07.035 |
| Popis: | The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC 50 456 μM) and Bacillus subtilis MraY (IC 50 386 μM), and which showed antimicrobial activity against B. subtilis (MIC 16 μg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC 50 32 μM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg 2+ cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9. |
| Databáze: | OpenAIRE |
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