Large-scale chemical-genetics yields new Mycobacterium tuberculosis inhibitor classes Institutional Repository Document uri icon


  • 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, measuring > 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 PROSPECTs ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.

altmetric score

  • 20.35

author list (cited authors)

  • Johnson, E. O., LaVerriere, E., Stanley, M., Office, E., Meyer, E., Kawate, T., ... Hung, D. T.

citation count

  • 0

complete list of authors

  • Johnson, Eachan O||LaVerriere, Emily||Stanley, Mary||Office, Emma||Meyer, Elisabeth||Kawate, Tomohiko||Gomez, James||Audette, Rebecca E||Bandyopadhyay, Nirmalya||Betancourt, Natalia||Delano, Kayla||Da Silva, Israel||Davis, Joshua||Gallo, Christina||Gardner, Michelle||Golas, Aaron||Guinn, Kristine M||Korn, Rebecca||McConnell, Jennifer A||Moss, Caitlin E||Murphy, Kenan C||Nietupski, Ray||Papavinasasundaram, Kadamba G||Pinkham, Jessica T||Pino, Paula A||Proulx, Megan K||Ruecker, Nadine||Song, Naomi||Thompson, Matthew||Trujillo, Carolina||Wakabayashi, Shoko||Wallach, Joshua B||Watson, Christopher||Ioerger, Thomas R||Lander, Eric S||Hubbard, Brian K||Serrano-Wu, Michael H||Ehrt, Sabine||Fitzgerald, Michael||Rubin, Eric J||Sassetti, Christopher M||Schnappinger, Dirk||Hung, Deborah T

Book Title

  • bioRxiv

publication date

  • August 2018