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

Author

Listed:
  • Eachan O. Johnson

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Emily LaVerriere

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Emma Office

    (Broad Institute of MIT and Harvard)

  • Mary Stanley

    (Broad Institute of MIT and Harvard
    Rush University Medical Center)

  • Elisabeth Meyer

    (Broad Institute of MIT and Harvard
    Stanford University)

  • Tomohiko Kawate

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • James E. Gomez

    (Broad Institute of MIT and Harvard)

  • Rebecca E. Audette

    (Harvard T. H. Chan School of Public Health
    Saint Louis University School of Medicine)

  • Nirmalya Bandyopadhyay

    (Broad Institute of MIT and Harvard)

  • Natalia Betancourt

    (Weill Cornell Medical College
    Regeneron Pharmaceuticals)

  • Kayla Delano

    (Broad Institute of MIT and Harvard)

  • Israel Silva

    (Weill Cornell Medical College)

  • Joshua Davis

    (Broad Institute of MIT and Harvard
    Regulatory and Quality Solutions LLC)

  • Christina Gallo

    (Broad Institute of MIT and Harvard
    Boston University School of Medicine)

  • 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
    Yale School of Medicine)

  • 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
    Caribou Biosciences)

  • 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
    University of Massachusetts Amherst)

  • 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
    Massachusetts General Hospital
    Harvard Medical School)

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.

Suggested Citation

  • 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, 2019. "Large-scale chemical–genetics yields new M. tuberculosis inhibitor classes," Nature, Nature, vol. 571(7763), pages 72-78, July.
    • Handle: RePEc:nat:nature:v:571:y:2019:i:7763:d:10.1038_s41586-019-1315-z
    DOI: 10.1038/s41586-019-1315-z
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    Cited by:

    1. Jing Gu & Rui-Kun Peng & Chun-Ling Guo & Meng Zhang & Jie Yang & Xiao Yan & Qian Zhou & Hongwei Li & Na Wang & Jinwei Zhu & Qin Ouyang, 2022. "Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Nadine Bongaerts & Zainab Edoo & Ayan A. Abukar & Xiaohu Song & Sebastián Sosa-Carrillo & Sarah Haggenmueller & Juline Savigny & Sophie Gontier & Ariel B. Lindner & Edwin H. Wintermute, 2022. "Low-cost anti-mycobacterial drug discovery using engineered E. coli," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Shuhui Wang & Kun Wang & Kangkang Song & Zon Weng Lai & Pengfei Li & Dongying Li & Yajie Sun & Ye Mei & Chen Xu & Maofu Liao, 2024. "Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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