Curcumin enhances bedaquiline’s efficacy against <i>Mycobacterium abscessus</i> : <i>in vitro</i> and <i>in vivo</i> evidence

In this study, we describe the combined effects of bedaquiline (BDQ) and the natural product curcumin (CUR) on <i>Mycobacterium abscessus</i>. In both <i>in vitro</i> and <i>in vivo</i> experiments, CUR enhanced BDQ's inhibitory effect. This combination reduced <i>M. abscessus</i> survival under nutrient-deprived, hypoxic, and acidic conditions, accelerated ATP depletion, mitigated BDQ-induced respiratory compensation, and effectively improved infection outcomes in both normal and immunosuppressed mice. Metabolomics analysis revealed that adding CUR to BDQ exacerbated BDQ-dependent downregulation of purine and pyrimidine metabolism and amino acid synthesis. Thus, BDQ-CUR combination therapy could potentially be applied to treat <i>M. abscessus</i> infections.IMPORTANCE<i>Mycobacterium abscessus</i> is an emerging pathogen that causes pulmonary infections, particularly in immunocompromised patients. It exhibits natural resistance to many anti-tuberculosis drugs, posing significant challenges for both patients and physicians, thereby raising the need for innovative drug discovery. Here, we describe the combined effects of bedaquiline (BDQ) and curcumin (CUR) on <i>M. abscessus</i>. <i>In vitro</i> and <i>in vivo</i> studies have shown that CUR enhances the inhibitory effect of BDQ. Additionally, we investigated the synergistic effects at the metabolic level. Thus, these findings highlight the potential of BDQ-CUR combination therapy against <i>M. abscessus</i> infections.