Evaluation of clofazimine-bedaquiline combination as a candidate regimen for macrolide-resistant <i>Mycobacterium avium</i> complex infection

The <i>Mycobacterium avium</i> complex (MAC) is the primary cause of pulmonary disease (PD) among nontuberculous mycobacteria, presenting a significant treatment challenge on a global scale. A long-term (≥12 months) three-drug regimen, typically including a macrolide, such as clarithromycin (CLR) or azithromycin, along with rifampicin and ethambutol, is recommended. However, many patients fail to respond adequately to therapy, and some eventually develop macrolide resistance, making the disease even more difficult to treat. This highlights the urgent need for improved therapeutic strategies. Here, we investigated the efficacy of clofazimine (CFZ) and bedaquiline (BDQ), both repurposed from multidrug-resistant tuberculosis therapy, against macrolide-resistant MAC. In macrophage infection assays, both CFZ and BDQ showed significant intracellular inhibitory activity against macrolide-resistant clinical isolates, with CFZ generally exhibiting stronger effects. In a chronic murine model of MAC-caused progressive PD, substitution of CLR with CFZ and BDQ in the treatment regimen led to marked reductions in bacterial loads in both lung and spleen compared with the standard regimen, achieving up to 0.86 log₁₀ CFU reduction in lung and 2.17 log₁₀ CFU in spleen tissues. These findings demonstrate that CFZ and BDQ retain potent activity against macrolide-resistant MAC and highlight their potential as promising components of alternative treatment regimens.