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 (29.4% each), followed by His445Asn (17.6%). RIF minimum inhibitory concentration (MIC) values ranged from <=0.25 to 1.0 mg/L, confirming low-level resistance. Notably, 52.9% (9/17) of the isolates were co-resistant to fluoroquinolones, and 23.5% (4/17) to isoniazid. According to WHO classification, 58.8% (10/17) were pre-extensively drug-resistant TB (Pre-XDR-TB) or multidrug-resistant TB (MDR-TB). Phylogenetic analysis revealed that 94.1% (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.