Genomic Characterization of XDR Mycobacterium tuberculosis Isolates in Argentina (2006-2015)

Background: Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, with Mtb being the second leading infectious killer worldwide, following COVID-19. Despite over a century of research, the disease continues to pose a major threat, with an estimated one-fourth of the global population latently infected. According to the World Health Organization (WHO), approximately 1.25 million deaths were attributed to TB in 2023 alone. The emergence of multidrug-resistant (MDR) strains, resistant to isoniazid and rifampin, and extensively drug-resistant (XDR) strains, resistant to isoniazid, rifampin, a fluoroquinolone, and a second-line injectable aminoglycoside, further complicates the situation, posing significant challenges for healthcare systems. In Argentina, TB burden is moderate compared to other countries, with approximately 10,500 new cases and 1,000 deaths reported annually. While standard therapy is generally effective, XDR Mtb infections require prolonged and costly treatment and are often associated with a guarded prognosis. Methods: In this work, we applied whole-genome sequencing analysis to investigate XDR strains circulating in Argentina between 2006 and 2015. Genotypic variants of each isolate were compared against resistance-associated variant databases and subjected to local and global phylogenetic analyses. Results: The analysis revealed no common origins for the most frequently observed resistance mutations. Notable variants associated with resistance to first-line drugs included katG Ser315Thr and fabG1 -15C < T for isoniazid, rpoB Ser450Leu and Asp435Val for rifampin, embB Gly406Ala, and Met306Ile for ethambutol, as well as multiple variants in the pncA gene linked to pyrazinamide resistance. Conclusions: This study provides valuable insights into the molecular mechanisms of antibiotic resistance in M. tuberculosis , specifically focusing on XDR strains circulating in Argentina. The findings highlight the genetic diversity and complexity of resistance-associated variants, emphasizing the need for continued research and surveillance efforts to address this pressing global health threat.