ArticleProceedings of the National Academy of Sciences of the United States of America2010
Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 127 citations in OpenAlex.
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- Antibiotic tolerance & resilience in M. tuberculosis: Potential to predict & pre-empt antibiotic resistance.The Indian journal of medical research · 2025Article
- The identification Mycobacterium tuberculosis genes that modulate long term survival in the presence of rifampicin and streptomycin.Scientific reports · 2025Article
- TnSeq identifies genetic requirements of Mycobacterium tuberculosis for survival under vaccine-induced immunity.NPJ vaccines · 2025Article
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- Composition and liquid-to-solid maturation of protein aggregates contribute to bacterial dormancy development and recovery.Nature communications · 2025Article
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- Steroid Drugs Inhibit Bacterial Respiratory Oxidases and Are Lethal Toward Methicillin-Resistant Staphylococcus aureus.The Journal of infectious diseases · 2024Article
- Gene Regulatory Mechanism of Mycobacterium Tuberculosis during Dormancy.Current issues in molecular biology · 2024Review
- Altered serine metabolism promotes drug tolerance inAntimicrobial agents and chemotherapy · 2024Article
- A virulence-associated small RNA MTS1338 activates an ABC transporter CydC for rifampicin efflux inFrontiers in microbiology · 2024Article
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- Uptake-independent killing of macrophages by extracellular Mycobacterium tuberculosis aggregates.The EMBO journal · 2023Article
- Mycobacterium tuberculosis Requires the Outer Membrane Lipid Phthiocerol Dimycocerosate for Starvation-Induced Antibiotic Tolerance.mSystems · 2023Article
- Biosynthesis of Isonitrile Lipopeptide Metallophores from Pathogenic Mycobacteria.Biochemistry · 2023Article
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- PrrA modulates Mycobacterium tuberculosis response to multiple environmental cues and is critically regulated by serine/threonine protein kinases.PLoS genetics · 2022Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Tuberculosis (TB) is notoriously difficult to cure, requiring administration of multiple antibiotics for 6 mo or longer. Conventional anti-TB drugs inhibit biosynthetic processes involved in cell growth and division, such as DNA replication, RNA transcription, protein translation, and cell wall biogenesis. Although highly effective against bacteria cultured in vitro under optimal growth conditions, these antibiotics are less effective against bacteria grown in vivo in the tissues of a mammalian host. The factors that contribute to the antibiotic tolerance of bacteria grown in vivo are unknown, although altered metabolism and sluggish growth are hypothesized to play a role. To address this question, we identified mutations in Mycobacterium tuberculosis that impaired or enhanced persistence in mice treated with isoniazid (INH), a front-line anti-TB drug. Disruption of cydC, encoding a putative ATP-binding cassette transporter subunit, accelerated bacterial clearance in INH-treated mice without affecting growth or survival in untreated mice. Conversely, transposon insertions within the rv0096-rv0101 gene cluster attenuated bacterial growth and survival in untreated mice but paradoxically prevented INH-mediated killing of bacteria in treated mice. These contrasting phenotypes were dependent on the interaction of the bacteria with the tissue environment because both mutants responded normally to INH when grown in macrophages ex vivo or in axenic cultures in vitro. Our findings have important implications because persistence-impairing mutations would be missed by conventional genetic screens to identify candidate drug targets. Conversely, persistence-enhancing mutations would be missed by standard diagnostic methods, which are performed on bacteria grown in vitro, to detect drug resistance.
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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.