ArticlePloS one2012
Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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.
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.
Who cites it
95 citing papers in PubMed, 230 citations in OpenAlex.
- Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Verapamil Suppresses the Development of Resistance Against Anti-Tuberculosis Drugs in Mycobacteria.International journal of molecular sciences · 2025Article
- Computational guided identification of novel anti-mycobacterial agent proved by in-vitro and in-vivo validation.BMC microbiology · 2025Article
- Whole-Genome Sequence Analysis to Assess Mutations in Efflux Pumps inMicroorganisms · 2025Article
- Investigation of potential relationship betweenmazEF3, relJK, and vapBC3 genes and antimicrobial resistance inMycobacterium bovis.BMC infectious diseases · 2025Article
- Innovative Strategies for Combating Multidrug-Resistant Tuberculosis: Advances in Drug Delivery Systems and Treatment.Microorganisms · 2025Review
- Dissemination of arr-2 and arr-3 is associated with class 1 integrons in Klebsiella pneumoniae clinical isolates from Portugal.Medical microbiology and immunology · 2025Article
- Genetic stability ofeLife · 2024Article
- Structure and function ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition.Nature communications · 2024Article
- EfpA is required for regrowth ofAntimicrobial agents and chemotherapy · 2024Article
- Overexpression of efflux pump genes is one of the mechanisms causing drug resistance inMicrobiology spectrum · 2024Article
- Structures of the essential efflux pump EfpA fromResearch square · 2024Article
- Exposure ofFrontiers in tuberculosis · 2024Article
- Understanding the Phage-Host Interaction Mechanism toward Improving the Efficacy of Current Antibiotics inBiomedicines · 2023Article
- C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol.Frontiers in antibiotics · 2023Article
- Proteome Profile Changes Induced by Heterologous Overexpression ofBiomolecules · 2022Article
- Novel Antibacterial Activity of Febuxostat, an FDA-Approved Antigout Drug against Mycobacterium tuberculosis Infection.Antimicrobial agents and chemotherapy · 2022Article
- Critical discussion on drug efflux in Mycobacterium tuberculosis.FEMS microbiology reviews · 2022Review
- Repurposing Based Identification of Novel Inhibitors against MmpS5-MmpL5 Efflux Pump ofBiomedicines · 2022Article
35 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.