ArticleScientific reports2023
Bedaquiline- and clofazimine- selected Mycobacterium tuberculosis mutants: further insights on resistance driven largely by Rv0678.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Global mapping of bedaquiline-resistant Mycobacterium tuberculosis: a systematic review.BMC infectious diseases · 2026Pooled it
- Recent advances in antituberculosis drugs and therapeutics: from mechanistic breakthroughs to clinical translation.Molecular biomedicine · 2026Review
- A Multi-Scale Computational Framework for Anti-Persister Tuberculosis Drug Discovery.Chemical biology & drug design · 2026Review
- No phenotypic resistance observed for most group-3 and -4 variants inMicrobiology spectrum · 2026Article
- Performance of a targeted next generation sequencing assay for mycobacterial identification and drug resistance from sputum and isolates.Journal of clinical microbiology · 2026Article
- Targeted next-generation sequencing implementation in Eswatini identifies rifampicin and bedaquiline resistance undetected by routine diagnostic testing.Nature communications · 2026Article
- Antibody-Antibiotic Conjugates: Mechanisms, Clinical Progress, and Next-Generation Strategies Against Multidrug-Resistant Bacterial Infections.MicrobiologyOpen · 2026Review
- Molecular Kaleidoscope of Nucleoid-Associated Proteins Regulatory Network and Chromosome Architecture in Mycobacterium Tuberculosis.Current microbiology · 2026Review
- Article
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- New drugs for the management of tuberculosis.Current opinion in infectious diseases · 2025Review
- Article
- Efflux pumps positively contribute to rifampin resistance in rpoB mutant Mycobacterium tuberculosis.Annals of clinical microbiology and antimicrobials · 2025Article
- An improved catalogue for whole-genome sequencing prediction of bedaquiline resistance inMicrobial genomics · 2025Article
- Verapamil and its metabolite norverapamil inhibit theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Direct thin-layer agar for bedaquiline-susceptibility testing ofJournal of clinical microbiology · 2025Article
- Country-level heterogeneity in MDR-TB drug susceptibility supports country-specific policy development.Frontiers in tuberculosis · 2025Article
- Frameshift mutations in theAntimicrobial agents and chemotherapy · 2024Article
- Genomic Characterization of Drug-ResistantAntibiotics (Basel, Switzerland) · 2023Article
- Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline againstFrontiers in medicine · 2023Review
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug-resistant tuberculosis is a serious global health threat. Bedaquiline (BDQ) is a relatively new core drug, targeting the respiratory chain in Mycobacterium tuberculosis (Mtb). While mutations in the BDQ target gene, atpE, are rare in clinical isolates, mutations in the Rv0678 gene, a transcriptional repressor regulating the efflux pump MmpS5-MmpL5, are increasingly observed, and have been linked to worse treatment outcomes. Nevertheless, underlying mechanisms of (cross)-resistance remain incompletely resolved. Our study aims to distinguish resistance associated variants from other polymorphisms, by assessing the in vitro onset of mutations under drug pressure, combined with their impact on minimum inhibitory concentrations (MICs) and on protein stability. For this purpose, isolates were exposed in vitro to sub-lethal concentrations of BDQ or clofazimine (CFZ). Selected colonies had BDQ- and CFZ-MICs determined on 7H10 and 7H11 agar. Sanger sequencing and additional Deeplex Myc-TB and whole genome sequencing (WGS) for a subset of isolates were used to search for mutations in Rv0678, atpE and pepQ. In silico characterization of relevant mutations was performed using computational tools. We found that colonies that grew on BDQ medium had mutations in Rv0678, atpE or pepQ, while CFZ-exposed isolates presented mutations in Rv0678 and pepQ, but none in atpE. Twenty-eight Rv0678 mutations had previously been described among in vitro selected mutants or in patients' isolates, while 85 were new. Mutations were scattered across the Rv0678 gene without apparent hotspot. While most Rv0678 mutations led to an increased BDQ- and/or CFZ-MIC, only a part of them surpassed the critical concentration (69.1% for BDQ and 87.9% for CFZ). Among the mutations leading to elevated MICs for BDQ and CFZ, we report a synonymous Val1Val mutation in the Rv0678 start codon. Finally, in silico characterization of Rv0678 mutations suggests that especially the C46R mutant may render Rv0678 less stable.
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