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

• Published in: Nature chemical biology Vol. 11; no. 4; pp. 292 - 298
• Main Authors: Landeta, Cristina, Blazyk, Jessica L, Hatahet, Feras, Meehan, Brian M, Eser, Markus, Myrick, Alissa, Bronstain, Ludmila, Minami, Shoko, Arnold, Holly, Ke, Na, Rubin, Eric J, Furie, Barbara C, Furie, Bruce, Beckwith, Jon, Dutton, Rachel, Boyd, Dana
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.04.2015
• Subjects: Agar - chemistry; Anti-Bacterial Agents - chemistry; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Catalytic Domain; Chemistry, Pharmaceutical - methods; Combinatorial Chemistry Techniques; Disulfides; Dose-Response Relationship, Drug; Drug Design; Electron Transport; Escherichia coli; Escherichia coli - metabolism; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - chemistry; Mass Spectrometry; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - chemistry; Microbial Sensitivity Tests; Mycobacterium smegmatis - metabolism; Mycobacterium tuberculosis; Mycobacterium tuberculosis - metabolism; Protein Conformation; Protein Disulfide-Isomerases - antagonists & inhibitors; Protein Disulfide-Isomerases - chemistry; Pseudomonas aeruginosa - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1752

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.