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PubMed2026

Genetic diversity of clinical Mycobacterium bovis BCG isolates from an immunocompromised patient with BCG infection.

BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine is widely administered to prevent severe tuberculosis but can cause serious adverse events, including disseminated BCGosis, in immunocompromised individuals. However, studies investigating the in vivo genetic adaptation and microevolution of this live-attenuated vaccine during prolonged infection remain limited. METHODS: Two clinical Mycobacterium bovis BCG isolates (BCG01 and BCG02) and a lot-matched vaccine strain (VAC) underwent whole-genome sequencing. Phenotypic drug susceptibility testing was performed on the clinical isolates. Genomic relatedness was assessed using SNP-distance clustering and maximum-likelihood phylogeny against global reference strains. Comparative variant analysis was performed to identify mutations specific to BCG01 and BCG02 relative to VAC, and genotypic drug resistance was assessed using TB-Profiler. RESULTS: Phylogenomic analyses and SNP distance confirmed that both clinical isolates were derived from the BCG Tokyo 172 vaccine strain. BCG02 exhibited twice the mutational burden of BCG01, acquiring mutations in genes associated with cell wall biosynthesis (mas, ppsA), regulatory adaptation (pknK, dnaA), and surface antigens (pecA, PE/PPE). Crucially, whereas BCG01 remained susceptible to first-line drugs, BCG02 acquired a canonical rpoB Ser450Leu mutation (100% frequency) and a heteroresistant inhA Ile194Thr mutation (13% frequency), resulting in multidrug-resistant (MDR) BCGosis. CONCLUSION: Although structurally stable, the BCG Tokyo 172 vaccine strain can undergo rapid, clinically significant microevolution and clonal selection within immunocompromised hosts. The in vivo acquisition of multidrug resistance underscores the critical need for pre-vaccination immune screening and comprehensive laboratory monitoring of BCG-associated adverse events.

BCGosis↗

PubMed2026

Patterns of Drug Resistance, Drug Resistance Conferring Mutations and Genomic DNA Methylation Revealed in Mycobacterium tuberculosis From South Africa.

Tuberculosis remains a major public health threat globally, with drug-resistant strains undermining treatment efficacy. We analyzed 126 Mycobacterium tuberculosis (M. tuberculosis) isolates with diverse drug resistance spectra and selected 35 for whole genome sequencing (WGS) using Illumina NextSeq, SMRT PacBio Onso and SMRT PacBio Revio sequencing platforms. The study aimed to characterize drug resistance profiles, compare short- and long-read sequencing performance, identify lineages among South African isolates, detect known drug resistance mutations and their lineage-specific patterns, and utilize long-read SMRT platforms for epigenetic profiling. Multiple drug resistance mutations were identified, some lineage-specific, and notably, East-African-Indian (EAI) Lineage 1 isolates often considered less pathogenic, showed significant potential for multidrug-resistance development, including higher fluoroquinolone resistance as compared to other lineages. Three DNA motifs with methylated adenines, namely CACGCaG, CtCCaG and GaTNNNNRtAC, were detected, with methylation patterns varying by lineage and strain due to mutations in the corresponding methyltransferases (MTases). A particularly notable finding was the stable maintenance of a genetic heterogeneity in the mamB MTase, performing methylation at CACGCaG motifs. These results highlight the combined role of genetic and epigenetic variation in M. tuberculosis adaptive evolution and underscore the value of integrating long-read sequencing into TB surveillance and research.

Mycobacterium tuberculosis↗

PubMed2026

Genomic insights into low-level rifampicin resistance mediated by borderline rpoB mutations in Mycobacterium tuberculosis: prevalence and phylogeny in Northeast China.

The emergence of low-level rifampicin (RIF) resistance in Mycobacterium tuberculosis poses a challenge to tuberculosis (TB) control, as it often leads to discordance between genotypic resistance detected by molecular assays (e.g., Xpert MTB/RIF) and phenotypic susceptibility in conventional drug susceptibility testing (DST). In this study, we performed whole-genome sequencing (WGS) on 17 clinical isolates from Changchun, Northeast China, which exhibited such discordance. All isolates harbored functional borderline mutations in the rpoB RRDR region, predominantly Leu452Pro and Leu430Pro (29% each), followed by His445Asn (18%). RIF minimum inhibitory concentration (MIC) values ranged from ≤0.25 to 1.0 mg/L, confirming low-level resistance. Notably, 53% (9/17) of the isolates were co-resistant to fluoroquinolones and 24% (4/17) to isoniazid (INH). According to WHO classification, 59% (10/17) were pre-extensively drug-resistant TB (Pre-XDR-TB) or multidrug-resistant TB (MDR-TB). Phylogenetic analysis revealed that 94% (16/17) belonged to the East Asian Beijing lineage (Lineage 2.2.1), with no evidence of recent local transmission. These findings underscore the complexity of low-level RIF resistance and its frequent association with broader drug resistance in a dominant lineage, highlighting the need for integrating MIC and WGS into diagnostic algorithms to guide appropriate treatment and surveillance.IMPORTANCEThe accurate detection of RIF resistance is critical for the management of TB, yet standard phenotypic methods often fail to identify strains with low-level resistance conferred by borderline rpoB mutations. This study provides the first genomic characterization of such discordant isolates in Northeast China, revealing a high prevalence of co-resistance to other key drugs and a strong association with the locally dominant Beijing lineage. The findings emphasize that reliance on phenotypic DST alone may lead to underestimation of drug resistance and inappropriate treatment, potentially contributing to the emergence and spread of Pre-XDR-TB and MDR-TB. Incorporating MIC determination and WGS into routine diagnostics could enhance detection, inform tailored therapy, and improve surveillance of these clinically significant strains.

Mycobacterium tuberculosis↗