Evidence map›Paper›PMID 42248880›Full record

ArticleNature communications2026

Genome scale CRISPRi reveals both shared and strain-specific vulnerabilities in genetically diverse drug-resistant strains of Mycobacterium tuberculosis.

XinYue Wang, William J Jowsey, Chen-Yi Cheung, Nina Dickerhof, Cassandra L Chapman, Jamie R H Taka, Mark B Hampton, Ghader Bashiri, Paul P Gardner, Peter C Fineran and 3 more

Abstract read
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–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

1 citing paper in PubMed.

  1. Article
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

13 authors.

XinYue WangDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.ORCID http://orcid.org/0000-0001-6990-783X
William J JowseyDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Chen-Yi CheungDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Nina DickerhofMātai Hāora - Centre for Redox Biology and Medicine, Department of Pathology and Molecular Medicine, University of Otago Christchurch, Christchurch, New Zealand.ORCID http://orcid.org/0000-0003-2269-4595
Cassandra L ChapmanDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Jamie R H TakaSchool of Biological Sciences, The University of Auckland, Auckland, New Zealand.
Mark B HamptonMātai Hāora - Centre for Redox Biology and Medicine, Department of Pathology and Molecular Medicine, University of Otago Christchurch, Christchurch, New Zealand.ORCID http://orcid.org/0000-0002-7349-3729
Ghader BashiriSchool of Biological Sciences, The University of Auckland, Auckland, New Zealand.ORCID http://orcid.org/0000-0002-5092-3749
Paul P GardnerDepartment of Biochemistry, University of Otago, Dunedin, New Zealand.ORCID http://orcid.org/0000-0002-7808-1213
Peter C FineranDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.ORCID http://orcid.org/0000-0002-4639-6704
Gregory M CookDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.ORCID http://orcid.org/0000-0001-8349-1500
Simon A JacksonMaurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.ORCID http://orcid.org/0000-0002-4512-3093
Matthew B McNeilDepartment of Microbiology and Immunology, University of Otago, Dunedin, New Zealand. matthew.mcneil@otago.ac.nz.ORCID http://orcid.org/0000-0001-7747-7745

Funding

Manatu Hauora | Health Research Council of New Zealand (HRC) 20/459Manatu Hauora | Health Research Council of New Zealand (HRC) 22/156Manatu Hauora | Health Research Council of New Zealand (HRC) 22/323Manatu Hauora | Health Research Council of New Zealand (HRC) 23/228
6 · The paper itself

Abstract

The global health burden caused by Mycobacterium tuberculosis is aggravated by the emergence and spread of drug resistance. Mutations that cause drug resistance can have collateral effects that increase the vulnerability of downstream pathways to inhibition. Here, using genome scale CRISPR interference we identified collateral effects associated with different drug-resistant genotypes of M. tuberculosis. We demonstrate that drug resistance generated shared vulnerabilities in several overlapping functional pathways. Most drug-resistant strains were more sensitive to tRNA synthetase knockdowns than the parental drug-sensitive strain, highlighting the potential of tRNA synthetases as high-value drug targets. Additionally, the rifampicin-resistant mutant RpoB(S450L) had increased sensitivity to the dysregulation of sulphur metabolism due to transcriptional dysregulation. This increased vulnerability did not translate to all rpoB genotypes but was linked to predicted effects on transcriptional dynamics. Amongst clinical isolates, non-synonymous mutations in sulphur metabolism genes have evolved in a geographic lineage specific manner to mitigate fitness costs associated with the collateral phenotypes of drug resistance. Combined, our findings highlight the power of functional genomics in pinpointing highly vulnerable drug targets across drug-resistant strains.

Indexed as

Drug Resistance, BacterialGenome, BacterialMycobacterium tuberculosisAmino Acyl-tRNA SynthetasesAntitubercular AgentsBacterial ProteinsCRISPR-Cas SystemsDNA-Directed RNA PolymerasesDrug Resistance, Multiple, BacterialGene Expression Regulation, BacterialGenotypeHumansMicrobial Sensitivity TestsMutationRifampinSulfurAmino Acyl-tRNA SynthetasesAntitubercular AgentsBacterial ProteinsDNA-Directed RNA PolymerasesRifampinrpoB protein, Mycobacterium tuberculosisSulfur

Identifiers

PMID42248880
PMCPMC13402693

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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.