A high-throughput screening campaign to identify inhibitors of DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD)
| Autor: | Trishal Patel, Amanda Haymond, Karen Villarroel, Brandon Schweibenz, Clark J. Mantooth, Haley Ball, Richard Young, Allyson Dailey, Cynthia S. Dowd, Claire Johnson, Jessica Bases, Chinchu Johny, Robin D. Couch, Tyrone Dowdy |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Yersinia pestis 030106 microbiology Cytidylyltransferase Biophysics Computational biology Biochemistry Article Chemical library 03 medical and health sciences chemistry.chemical_compound High-Throughput Screening Assays Enzyme Inhibitors Molecular Biology Aldose-Ketose Isomerases Natural product Molecular Structure Pilot scale Cell Biology Mycobacterium tuberculosis Nucleotidyltransferases Recombinant Proteins DXP reductoisomerase Anti-Bacterial Agents 030104 developmental biology chemistry Antibacterial resistance |
| Zdroj: | Analytical biochemistry. 542 |
| ISSN: | 1096-0309 |
| Popis: | The rise of antibacterial resistance among human pathogens represents a problem that could change the landscape of healthcare unless new antibiotics are developed. The methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for novel antibiotic design, considering each enzyme of the pathway is both essential and has no human homologs. Here we describe a pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Hit compounds were characterized to deduce their mechanism of inhibition; most function through aggregation. The HTS workflow outlined here is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. |
| Databáze: | OpenAIRE |
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