<span class="word">From <span class="word">Mutation <span class="word">to <span class="word">Community <span class="word">Action: <span class="word">Drug-<span class="word">Resistance <span class="word">Patterns <span class="word">of <em><span class="word italic">Mycobacterium <span class="word italic">tuberculosis</em> <span class="word">in <span class="word">the <span class="word">Rural <span class="word">Eastern <span class="word">Cape, <span class="word">South <span class="word">Africa

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge and a leading infectious cause of death, with 10.6 million cases and 450,000 rifampicin-resistant cases reported in 2021. The rise of multi-drug-resistant (MDR) and extensively drug-resistant TB (XDR-TB), driven by mutations in genes such as rpoB, katG, inhA, gyrA, and rrs, threatens the practical control of TB. In the Eastern Cape, South Africa, limited data exist on the patterns of resistance-conferring mutations. This study investigated the molecular profiles of genetic mutations associated with first-line and second-line anti-tuberculosis drug resistance, including fluoroquinolones and injectable agents, among Mycobacterium tuberculosis isolates to inform region-specific diagnostics and treatment strategies. Methods: A retrospective cross-sectional laboratory-based design was used to analyze 112 phenotypically confirmed drug-resistant isolates. Molecular DST for first- and second-line anti-tuberculosis drugs was performed at the National Health Laboratory Service (NHLS) TB reference laboratory. Drug-resistance profiles were classified according to World Health Organization (WHO) definitions. Results: rpoB (D435V 40.2%; S450L 36.6%) and katG (S315T 80.4%) mutations predominated, forming the MDR backbone, while 15% harbored inhA promoter mutations linked to low-level cross-resistance. Nearly 48.2% showed dual resistance to fluoroquinolones and second-line injectables. A significant association between rpoB S450L and dual second-line resistance (p=0.0019) suggests genomic progression toward XDR-TB. The predominance of stable high-fitness resistance mutations and the substantial burden of dual second-line resistance suggest sustained community transmission of established multidrug-resistant strains. These findings underscore the importance of integrating molecular surveillance with community-engaged prevention strategies and strengthened clinical governance to interrupt transmission and limit progression toward advanced resistance in high-burden rural settings. They further reinforce the value of genotype-based diagnostics and expanded genomic surveillance within routine TB programs. Incorporating predictive analytics into programmatic practice will enhance early detection, optimize treatment selection, and support sustained progress toward TB control and eventual elimination.