Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria
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Blazyk, Jessica L.
Hatahet, Feras
Eser, Markus
Bronstain, Ludmila
Arnold, Holly
Ke, Na
Beckwith, Jon
Dutton, Rachel
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nchembio.1752Metadata
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Landeta, C., J. L. Blazyk, F. Hatahet, B. M. Meehan, M. Eser, A. Myrick, L. Bronstain, et al. 2015. “Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria.” Nature chemical biology 11 (4): 292-298. doi:10.1038/nchembio.1752. http://dx.doi.org/10.1038/nchembio.1752.Abstract
In bacteria, disulfide bonds confer stability on many proteins exported to the cell envelope or beyond. These proteins include numerous bacterial virulence factors. Thus, bacterial enzymes that promote disulfide bond formation represent targets for compounds inhibiting bacterial virulence. Here, we describe a novel target- and cell-based screening methodology for identifying compounds that inhibit the disulfide bond-forming enzymes E. coli DsbB (EcDsbB) or M. tuberculosis VKOR (MtbVKOR). MtbVKOR can replace EcDsbB although the two are not homologues. 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 E. coli growth. Furthermore, these compounds inhibit all but one of the DsbBs of nine other gram-negative pathogenic bacteria tested.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366281/pdf/Terms of Use
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