Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues

Abstract The increasing emergence of antimicrobial resistance (AMR) is reducing the effectiveness of existing antibiotics against bacterial infections, including tuberculosis (TB), a deadly disease caused by Mycobacterium tuberculosis (M.tb). Approximately 90% of infected individuals develop latent tuberculosis infection, for which current treatment options are limited. Latent tuberculosis infection is characterised by the formation of hypoxic granulomas, which restrict oxygen and drug penetration, highlighting the need for therapies effective under hypoxic conditions. In this study, a hypoxia-activated prodrug (HAP) strategy was employed to improve selective drug delivery of promising anti-tuberculosis drugs bedaquiline, TBAJ-587 and TBAJ-876 (sorfequiline) to hypoxic TB granulomas. Thirty-six nitroimidazole-based hypoxia-activated prodrugs (HAPs) were successfully synthesized and evaluated for antitubercular activity. The HAPs exhibited potent in vitro activity under both oxic and hypoxic conditions, with consistently lower MIC values observed in the hypoxic assays. Assessment of hypoxic selectivity demonstrated enhanced trigger cleavage under hypoxic conditions, providing strong evidence for the hypoxia-selective activation of these compounds. Collectively, these findings highlight the therapeutic potential of hypoxia-mediated strategies for the treatment of latent tuberculosis, particularly within hypoxic niches that drive disease persistence and prolonged treatment regimens.