Assessment of TB47 as a potential novel therapeutic agent: <i>in vitro</i> and <i>in vivo</i> efficacy against <i>Mycobacterium leprae</i>

Leprosy is a chronic infectious disease caused by <i>Mycobacterium leprae</i> and <i>Mycobacterium lepromatosis</i>. The treatment typically involves multidrug therapy comprising dapsone, clofazimine, and rifampicin for 6-12 months. TB47 is a new inhibitor of the mycobacterial electron transport chain (ETC), disrupting ATP production in bacteria. This study investigated the <i>in vitro</i> and <i>in vivo</i> antimicrobial effects of TB47 on <i>M. leprae. In vitro</i> assays employed IDE8 tick cells infected with <i>M. leprae</i>, showing that after 30 days of infection, 5 ng/mL of TB47 treatment significantly impaired bacillary growth. For <i>in vivo</i> assays, BALB/c mice were infected with <i>M. leprae</i> and subjected to different treatments with varying doses of TB47 combined or not with clofazimine. Treatments were administered weekly for 90 days (13 times). The effects were assessed immediately after treatment, as well as at 120 and 210 days post-treatment. Results showed that 100 and 10 mg/kg of TB47 combined with 5 mg/kg clofazimine exhibited a bactericidal effect on <i>M. leprae</i> in all time points evaluated, in contrast with clofazimine monotherapy, for which the bactericidal effect was observed only 210 days post-treatment. TB47 monotherapy had a bacteriostatic effect immediately after treatment, but replication resumed at later evaluation points. Histopathological evaluation supported these findings. Combining dose-dependent TB47 with clofazimine showed an additive bacteriostatic and bactericidal effect on <i>M. leprae</i>, suggesting an advantageous pharmacokinetic and pharmacodynamic profile. Further research into mycobacterial ETC inhibitors could significantly impact leprosy management by providing more effective and shorter treatment options.