Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria
| Autor: | Dana Boyd, Holly K. Arnold, Ludmila Bronstain, Brian M. Meehan, Shoko Minami, Cristina Landeta, Eric J. Rubin, Na Ke, Alissa Myrick, Feras Hatahet, Rachel J. Dutton, Jessica L. Blazyk, Bruce Furie, Barbara C. Furie, Jon Beckwith, Markus Eser |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Gram-negative bacteria
Protein Conformation Chemistry Pharmaceutical Mycobacterium smegmatis Protein Disulfide-Isomerases Microbial Sensitivity Tests Biology medicine.disease_cause Article Mass Spectrometry Microbiology Electron Transport Protein structure Bacterial Proteins Catalytic Domain medicine Escherichia coli Combinatorial Chemistry Techniques Disulfides Structural motif Protein disulfide-isomerase Molecular Biology Dose-Response Relationship Drug Escherichia coli Proteins Membrane Proteins Pathogenic bacteria Cell Biology Mycobacterium tuberculosis biology.organism_classification 3. Good health Anti-Bacterial Agents Agar Biochemistry Drug Design Pseudomonas aeruginosa Cell envelope Bacteria |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | In bacteria, disulfide bonds confer stability on many proteins exported to the cell envelope or beyond. These proteins include numerous bacterial virulence factors, and thus bacterial enzymes that promote disulfide bond formation represent targets for compounds inhibiting bacterial virulence. Here, we describe a new target- and cell-based screening methodology for identifying compounds that inhibit the disulfide bond-forming enzymes Escherichia coli DsbB (EcDsbB) or Mycobacterium tuberculosis VKOR (MtbVKOR), which can replace EcDsbB, although the two are not homologs. Initial screening of 51,487 compounds yielded six specifically inhibiting EcDsbB. These compounds share a structural motif and do not inhibit MtbVKOR. A medicinal chemistry approach led us to select related compounds, some of which are much more effective DsbB inhibitors than those found in the screen. These compounds inhibit purified DsbB and prevent anaerobic growth of E. coli. Furthermore, these compounds inhibit all but one of the DsbBs of nine other Gram-negative pathogenic bacteria tested. |
| Databáze: | OpenAIRE |
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