ArticleAntimicrobial agents and chemotherapy2016
Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 4 of them syntheses that pooled it.
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Who cites it
116 citing papers in PubMed, 4 syntheses or guidelines pooled it, 209 citations in OpenAlex.
- Global research trends in tuberculosis drug-resistance mechanisms: a bibliometric and cross-database analysis.Frontiers in microbiology · 2026Pooled it
- Genetic variants and their association with phenotypic resistance to bedaquiline inThe Lancet. Microbe · 2021Pooled it
- Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.The Journal of antimicrobial chemotherapy · 2020Pooled it
- Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.American journal of respiratory and critical care medicine · 2019Guideline
- ComparativeMicrobiology spectrum · 2026Article
- Molecular Mechanisms Underlying Antimicrobial Resistance in Mycobacteria.International journal of molecular sciences · 2026Review
- Bedaquiline resistance: a predictable consequence of a game-changing drug?ASM case reports · 2026Article
- Machine learning method for the prediction of Bedaquiline-resistantLife science alliance · 2026Article
- A Case of Transmission of Bedaquiline- and Linezolid-Resistant Tuberculosis.International journal of molecular sciences · 2026Article
- Berberine Attenuates Chromobacterium violaceum's Virulence by Targeting Efflux and Denitrification Machinery.Chemistry & biodiversity · 2026Article
- Mechanisms of Enhanced Low-Temperature Lignocellulose Degradation by an ARTP-InducedMicroorganisms · 2026Article
- Acquisition of bedaquiline and clofazimine resistance in association with a novel loss-of-function mutation in theASM case reports · 2026Article
- Bedaquiline Resistance: A Looming Global Threat in Tuberculosis Management.Current microbiology · 2025Review
- Analysis of Adverse Drug Reactions of Clofazimine Reported in the FDA Adverse Event Reporting System from 2004 to 2025 Q1.Infectious diseases and therapy · 2025Article
- Examination of Genetic Mutations of Clofazimine Resistance in Drug-Resistant Mycobacterium TB Isolates.Current microbiology · 2025Article
- Berberine, the major bioactive compound frombioRxiv : the preprint server for biology · 2025Article
- Vitamin C potentiates the killing ofmBio · 2025Article
- Sudapyridine (WX-081) inhibitsmSphere · 2025Article
- Efficacy of novel regimens targeting oxidative phosphorylation inAntimicrobial agents and chemotherapy · 2025Article
- Direct thin-layer agar for bedaquiline-susceptibility testing ofJournal of clinical microbiology · 2025Article
56 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
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