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Wakabayashi, Shoko

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Wakabayashi

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Shoko

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Wakabayashi, Shoko

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2015 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.7feedc25-8eac-4a77-a068-3e1a4e9518db

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    Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria
    (2015) Landeta, Cristina; Blazyk, Jessica L.; Hatahet, Feras; Meehan, Brian M.; Eser, Markus; Myrick, Alissa; Bronstain, Ludmila; Wakabayashi, Shoko; Arnold, Holly; Ke, Na; Rubin, Eric; Furie, Barbara; Furie, Bruce; Beckwith, Jon; Dutton, Rachel; Boyd, Dana
    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.
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    Large-Scale Chemical–genetics Yields New M. Tuberculosis Inhibitor Classes
    (Springer Science and Business Media LLC, 2019-06-19) LaVerriere, Emily; Meyer, Elisabeth; Kawate, Tomohiko; Gomez, James; Gardner, Michelle; Cigarroa Kennedy, Sofia; Wakabayashi, Shoko; Watson, Christopher; Fitzgerald, Michael; Johnson, Eachan; Office, Emma; Stanley, Mary; Audette, Rebecca; Bandyopadhyay, Nirmalya; Betancourt, Natalia; Delano, Kayla; Da Silva, Israel; Davis, Joshua; Gallo, Christina; Golas, Aaron; Guinn, Kristine; Korn, Rebecca; McConnell, Jennifer; Moss, Caitlin; Murphy, Kenan; Nietupski, Raymond; Papavinasasundaram, Kadamba; Pinkham, Jessica; Pino, Paula; Proulx, Megan; Ruecker, Nadine; Song, Naomi; Thompson, Matthew; Trujillo, Carolina; Metcalf-Wallach, Joshua; Ioerger, Thomas; Lander, Eric; Hubbard, Brian; Serrano-Wu, Michael; Ehrt, Sabine; Rubin, Eric; Sassetti, Christopher; Schnappinger, Dirk; Hung, Deborah
    New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, probing >8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified >40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating PROSPECT’s ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.