Large-scale chemical–genetics yields new M. tuberculosis inhibitor classes

Eachan O. Johnson, Emily LaVerriere, Emma Office, Mary Stanley, Elisabeth Meyer, Tomohiko Kawate, James E. Gomez, Rebecca E. Audette, Nirmalya Bandyopadhyay, Natalia Betancourt, Kayla Delano, Israel Silva, Joshua Davis, Christina Gallo, Michelle Gardner, Aaron J. Golas, Kristine M. Guinn, Sofia Kennedy, Rebecca Korn, Jennifer A. McConnell, Caitlin E. Moss, Kenan C. Murphy, Raymond M. Nietupski, Kadamba G. Papavinasasundaram, Jessica T. Pinkham, Paula A. Pino, Megan K. Proulx, Nadine Ruecker, Naomi Song, Matthew Thompson, Carolina Trujillo, Shoko Wakabayashi, Joshua B. Wallach, Christopher Watson, Thomas R. Ioerger, Eric S. Lander, Brian K. Hubbard, Michael H. Serrano-Wu, Sabine Ehrt, Michael Fitzgerald, Eric J. Rubin, Christopher M. Sassetti, Dirk Schnappinger and Deborah T. Hung ()
Additional contact information
Eachan O. Johnson: Broad Institute of MIT and Harvard
Emily LaVerriere: Broad Institute of MIT and Harvard
Emma Office: Broad Institute of MIT and Harvard
Mary Stanley: Broad Institute of MIT and Harvard
Elisabeth Meyer: Broad Institute of MIT and Harvard
Tomohiko Kawate: Broad Institute of MIT and Harvard
James E. Gomez: Broad Institute of MIT and Harvard
Rebecca E. Audette: Harvard T. H. Chan School of Public Health
Nirmalya Bandyopadhyay: Broad Institute of MIT and Harvard
Natalia Betancourt: Weill Cornell Medical College
Kayla Delano: Broad Institute of MIT and Harvard
Israel Silva: Weill Cornell Medical College
Joshua Davis: Broad Institute of MIT and Harvard
Christina Gallo: Broad Institute of MIT and Harvard
Michelle Gardner: Harvard T. H. Chan School of Public Health
Aaron J. Golas: Broad Institute of MIT and Harvard
Kristine M. Guinn: Harvard T. H. Chan School of Public Health
Sofia Kennedy: Broad Institute of MIT and Harvard
Rebecca Korn: Broad Institute of MIT and Harvard
Jennifer A. McConnell: Weill Cornell Medical College
Caitlin E. Moss: University of Massachusetts Medical School
Kenan C. Murphy: University of Massachusetts Medical School
Raymond M. Nietupski: Broad Institute of MIT and Harvard
Kadamba G. Papavinasasundaram: University of Massachusetts Medical School
Jessica T. Pinkham: Harvard T. H. Chan School of Public Health
Paula A. Pino: Weill Cornell Medical College
Megan K. Proulx: University of Massachusetts Medical School
Nadine Ruecker: Weill Cornell Medical College
Naomi Song: Weill Cornell Medical College
Matthew Thompson: Broad Institute of MIT and Harvard
Carolina Trujillo: Weill Cornell Medical College
Shoko Wakabayashi: Harvard T. H. Chan School of Public Health
Joshua B. Wallach: Weill Cornell Medical College
Christopher Watson: Broad Institute of MIT and Harvard
Thomas R. Ioerger: Texas A&M University
Eric S. Lander: Broad Institute of MIT and Harvard
Brian K. Hubbard: Broad Institute of MIT and Harvard
Michael H. Serrano-Wu: Broad Institute of MIT and Harvard
Sabine Ehrt: Weill Cornell Medical College
Michael Fitzgerald: Broad Institute of MIT and Harvard
Eric J. Rubin: Harvard T. H. Chan School of Public Health
Christopher M. Sassetti: University of Massachusetts Medical School
Dirk Schnappinger: Weill Cornell Medical College
Deborah T. Hung: Broad Institute of MIT and Harvard

Nature, 2019, vol. 571, issue 7763, 72-78

Abstract: Abstract New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100–150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical–genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical–genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.

Date: 2019
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DOI: 10.1038/s41586-019-1315-z

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