PT  - JOURNAL ARTICLE
AU  - Eachan O. Johnson
AU  - Emily LaVerriere
AU  - Mary Stanley
AU  - Emma Office
AU  - Elisabeth Meyer
AU  - Tomohiko Kawate
AU  - James Gomez
AU  - Rebecca E. Audette
AU  - Nirmalya Bandyopadhyay
AU  - Natalia Betancourt
AU  - Kayla Delano
AU  - Israel Da Silva
AU  - Joshua Davis
AU  - Christina Gallo
AU  - Michelle Gardner
AU  - Aaron Golas
AU  - Kristine M. Guinn
AU  - Rebecca Korn
AU  - Jennifer A. McConnell
AU  - Caitlin E. Moss
AU  - Kenan C. Murphy
AU  - Ray Nietupski
AU  - Kadamba G. Papavinasasundaram
AU  - Jessica T. Pinkham
AU  - Paula A. Pino
AU  - Megan K. Proulx
AU  - Nadine Ruecker
AU  - Naomi Song
AU  - Matthew Thompson
AU  - Carolina Trujillo
AU  - Shoko Wakabayashi
AU  - Joshua B. Wallach
AU  - Christopher Watson
AU  - Thomas R. Ioerger
AU  - Eric S. Lander
AU  - Brian K. Hubbard
AU  - Michael H. Serrano-Wu
AU  - Sabine Ehrt
AU  - Michael Fitzgerald
AU  - Eric J. Rubin
AU  - Christopher M. Sassetti
AU  - Dirk Schnappinger
AU  - Deborah T. Hung
TI  - Large-scale chemical-genetics yields new <em>Mycobacterium tuberculosis</em> inhibitor classes
AID  - 10.1101/396440
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 396440
4099  - http://biorxiv.org/content/early/2019/01/16/396440.short
4100  - http://biorxiv.org/content/early/2019/01/16/396440.full
AB  - 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 PROSPECT’s ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.