Genome-wide analyses of Mycobacterium tuberculosis complex isolates reveal insights into circulating lineages and drug resistance mutations in The Gambia

Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex (MTBC), remains a pressing global health challenge, with the West African region, including The Gambia, experiencing a substantial burden. This study explores the genetic diversity of MTBC strains circulating in The Gambia for nearly two decades (2002–2021) to enhance understanding of drug resistance dynamics and inform targeted diagnostic and treatment strategies. Using whole-genome sequencing (WGS) data from 1,803 TB isolates, we identified the predominance of lineage 4 (L4, 67.2%) and lineage 6 (L6, 26.6%) strains, with L4 showing more significant genetic variability over time. Drug susceptibility analysis of these isolates revealed that 78% (1421 isolates) were drug-susceptible, while 6.5% (119 isolates) exhibited resistance, primarily to isoniazid, rifampicin, and their combination. Additionally, 15.5% (282 isolates) were classified as Other, having potential drug-resistance mutations of uncertain significance by the WHO catalogue. Interestingly, our resistance-associated analysis showed the lineage 6 specific ethambutol uncertain significance (by WHO catalogue) mutation (embC Ala307Thr) more prevalent in The Gambia than in West Africa and globally. Structural analysis showed that first-line drug resistance mutations frequently occur in solvent-inaccessible and conserved regions of proteins, often impacting protein stability and reflecting a balance between resistance, fitness, and evolutionary adaptation. This study highlights the coexistence of globally prevalent and regionally restricted MTBC lineages, underscoring the importance of region-specific TB control measures. Integrating bioinformatic and structural analyses revealed many uncertain significant mutations by the WHO catalogue in The Gambian isolates compared to West Africa and globally. These findings reinforce the necessity of continuous genomic surveillance to address the evolving challenges of TB in high-burden settings like West Africa.