ArticleThe Journal of antimicrobial chemotherapy2009
Resistant mutants of Mycobacterium tuberculosis selected in vitro do not reflect the in vivo mechanism of isoniazid resistance.
Article in The Journal of antimicrobial chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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49 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
- Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis.The Journal of antimicrobial chemotherapy · 2014Pooled it
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- The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis.Nature communications · 2023Article
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- Drug Degradation Caused byAntimicrobial agents and chemotherapy · 2022Article
- Evolution ofFrontiers in cellular and infection microbiology · 2022Review
- An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis.Communications biology · 2021Article
- The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis.FEMS microbiology reviews · 2021Review
- Development of a penem antibiotic against Mycobacteroides abscessus.Communications biology · 2020Article
- Characterization of Large Deletion Mutants of Mycobacterium tuberculosis Selected for Isoniazid Resistance.Antimicrobial agents and chemotherapy · 2020Article
- Identification of novel scaffolds targeting Mycobacterium tuberculosis.Journal of molecular medicine (Berlin, Germany) · 2019Article
- Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges.Genome medicine · 2019Review
- Chemical disarming of isoniazid resistance inProceedings of the National Academy of Sciences of the United States of America · 2019Article
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesThe high prevalence of isoniazid-resistant Mycobacterium tuberculosis is often explained by a high mutation rate for this trait, although detailed information to support this theory is absent. We studied the development of isoniazid resistance in vitro, making use of a laboratory strain of M. tuberculosis.
methodsSpontaneous isoniazid-resistant mutants were characterized by molecular methods allowing identification of the most commonly encountered resistance-conferring mutations. Additionally, we determined the in vitro mutation rates for isoniazid and rifampicin resistance, and characterized the genome of a triple-resistant strain.
resultsResults confirm that the in vitro mutation rate for isoniazid resistance (3.2 x 10(-7) mutations/cell division) is much higher than the rate for rifampicin resistance (9.8 x 10(-9) mutations/cell division). However, in the majority of the in vitro mutants katG was partially or completely deleted and neither of the two most common in vivo mutations, katG-S315T or inhA-C(-)15T, were found in 120 isogenic mutants. This implies that clinically prevalent resistance mutations were present in <0.8% of isoniazid-resistant strains selected in vitro (95% CI 0%-2.5%). The triple-resistant strain had acquired isoniazid resistance via a 49 kbp deletion, which included katG. Apart from previously identified resistance-conferring mutations, three additional point mutations were acquired during sequential selection steps.
conclusionsThese outcomes demonstrate that the in vivo mechanism of isoniazid resistance is not reflected by in vitro experiments. We therefore conclude that the high in vitro mutation rate for isoniazid resistance is not a satisfactory explanation for the fact that isoniazid monoresistance is significantly more widespread than monoresistance to rifampicin.
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