Evidence map›Paper›PMID 31217586›Full record

ArticleNature2019

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 and 34 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
102citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

102 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Article
  4. Oligonucleotide genetics forbioRxiv : the preprint server for biology · 2026
    Article
  5. Review
  6. Journal of bacteriology · 2026
    Review
  7. Article
  8. An activator of a two-component system controls cell separation and intrinsic drug resistance inProceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  9. Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Review
  17. Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  18. Article
  19. Review
  20. Article

42 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

44 authors.

Eachan O JohnsonBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Emily LaVerriereBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Emma OfficeBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Mary StanleyBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Elisabeth MeyerBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Tomohiko KawateBroad Institute of MIT and Harvard, Cambridge, MA, USA.
James E GomezBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Rebecca E AudetteDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Nirmalya BandyopadhyayBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Natalia BetancourtDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Kayla DelanoBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Israel Da SilvaDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Joshua DavisBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Christina GalloBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Michelle GardnerDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Aaron J GolasBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristine M GuinnDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Sofia KennedyBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Rebecca KornBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Jennifer A McConnellDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Caitlin E MossDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Kenan C MurphyDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Raymond M NietupskiBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Kadamba G PapavinasasundaramDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Jessica T PinkhamDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Paula A PinoDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Megan K ProulxDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Nadine RueckerDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Naomi SongDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Matthew ThompsonBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Carolina TrujilloDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Shoko WakabayashiDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Joshua B WallachDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Christopher WatsonBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Thomas R IoergerDepartment of Computer Science, Texas A&M University, College Station, TX, USA.
Eric S LanderBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Brian K HubbardBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Michael H Serrano-WuBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Sabine EhrtDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Michael FitzgeraldBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Eric J RubinDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Christopher M SassettiDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Dirk SchnappingerDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Deborah T HungBroad Institute of MIT and Harvard, Cambridge, MA, USA. dhung@broadinstitute.org.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Gene DeletionAntitubercular AgentsDNA GyraseDrug DiscoveryDrug Resistance, MicrobialFolic AcidMicrobial Sensitivity TestsMolecular Targeted TherapyMycobacterium tuberculosisMycolic AcidsReproducibility of ResultsSmall Molecule LibrariesSubstrate SpecificityTopoisomerase II InhibitorsTryptophanTuberculosisAntitubercular AgentsDNA GyraseFolic AcidMycolic AcidsSmall Molecule LibrariesTopoisomerase II InhibitorsTryptophan

Identifiers

PMID31217586

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.