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Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria

2015; Nature Portfolio; Volume: 11; Issue: 4 Linguagem: Inglês

10.1038/nchembio.1752

1552-4469

Cristina Landeta, Jessica L. Blazyk, Feras Hatahet, Brian Meehan, Markus Eser, Alissa Myrick, Ludmila Bronstain, Shoko Minami, Holly K. Arnold, Na Ke, Eric J. Rubin, Barbara C. Furie, Bruce Furie, Jon Beckwith, Rachel J. Dutton, Dana Boyd,

Bacterial biofilms and quorum sensing

A screen for compounds that inhibit disulfide bond formation in β-galactosidase in Escherichia coli found inhibitors of the membrane enzyme DsbB. Given the importance of DsbB in bacterial virulence, the inhibitors are potentially useful as antibacterials. 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.