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Nat Chem Biol. 2015 Apr;11(4):292-8. doi: 10.1038/nchembio.1752. Epub 2015 Feb 16.

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

Author information

1
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
3
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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.

PMID:
25686372
PMCID:
PMC4366281
DOI:
10.1038/nchembio.1752
[Indexed for MEDLINE]
Free PMC Article

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