ArticleAntimicrobial agents and chemotherapy2011
Precise null deletion mutations of the mycothiol synthesis genes reveal their role in isoniazid and ethionamide resistance in Mycobacterium smegmatis.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 52 citations in OpenAlex.
- Pharmacological targeting of the mycothiol cysteine ligase MshC in Mycobacteriumabscessus.The Journal of biological chemistry · 2026Article
- Host oxidative stress primes mycobacteria for rapid antibiotic resistance evolution.Nature communications · 2026Article
- Convolutional neural networks quantify antibiotic resistance in Mycobacterium tuberculosis with diagnostic grade accuracy and predict treatment response.Nature communications · 2026Article
- A Comprehensive Review of Genetic Mechanisms ofInfection and drug resistance · 2026Review
- Host oxidative stress primes mycobacteria for rapid antibiotic resistance evolution.Research square · 2025Article
- The efflux pumps Rv1877 and Rv0191 play differential roles in the protection ofFrontiers in microbiology · 2024Article
- TheRSC medicinal chemistry · 2023Article
- Molecular Determinants of Ethionamide Resistance in Clinical Isolates ofAntibiotics (Basel, Switzerland) · 2022Article
- Identification of drivers of mycobacterial resistance to peptidoglycan synthesis inhibitors.Frontiers in microbiology · 2022Article
- Transcriptional regulation and drug resistance inFrontiers in cellular and infection microbiology · 2022Review
- Polycysteine-encoding leaderless short ORFs function as cysteine-responsive attenuators of operonic gene expression in mycobacteria.Molecular microbiology · 2020Article
- Generation and characterization of thiol-deficient Mycobacterium tuberculosis mutants.Scientific data · 2018Article
- The functional interplay of low molecular weight thiols in Mycobacterium tuberculosis.Journal of biomedical science · 2018Article
- Host-pathogen redox dynamics modulate Mycobacterium tuberculosis pathogenesis.Pathogens and disease · 2018Article
- Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2017Article
- Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics.Cell chemical biology · 2017Article
- Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.PLoS pathogens · 2016Article
- Imaging the NADH:NADFrontiers in cellular and infection microbiology · 2016Article
- Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates.Antimicrobial agents and chemotherapy · 2015Article
- A GntR family transcription factor positively regulates mycobacterial isoniazid resistance by controlling the expression of a putative permease.BMC microbiology · 2015Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Mycothiol (MSH; AcCys-GlcN-Ins) is the glutathione analogue for mycobacteria. Mutations in MSH biosynthetic genes have been associated with resistance to isoniazid (INH) and ethionamide (ETH) in mycobacteria, but rigorous genetic studies are lacking, and those that have been conducted have yielded different results. In this study, we constructed independent null deletion mutants for all four genes involved in the MSH biosynthesis pathway (mshA, mshB, mshC, and mshD) in Mycobacterium smegmatis and made complementing constructs in integrating plasmids. The resulting set of strains was analyzed for levels of MSH, INH resistance, and ETH resistance. The mshA and mshC single deletion mutants were devoid of MSH production and resistant to INH, whereas the mshB deletion mutant produced decreased levels of MSH yet was sensitive to INH, suggesting that MSH biosynthesis is essential for INH susceptibility in M. smegmatis. Further evidence supporting this conclusion was generated by deleting the gene encoding the MSH S-conjugate amidase (mca) from the ΔmshB null mutant. This double mutant, ΔmshB Δmca, completely abolished MSH production and was resistant to INH. The mshA, mshC, and mshB single deletion mutants were also resistant to ETH, indicating that ETH resistance is modulated by the level of MSH in M. smegmatis. Surprisingly, the mshD deletion mutant lacked MSH production but was sensitive to both INH and ETH. The drug sensitivity was likely mediated by the compensated synthesis of N-formyl-Cys-GlcN-Ins, previously demonstrated to substitute for MSH in an mshD mutant of M. smegmatis. We conclude that MSH or N-formyl-Cys-GlcN-Ins is required for susceptibility to INH or ETH in M. smegmatis.
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