Vitamin C potentiates the killing of Mycobacterium tuberculosis by bedaquiline through metabolic disruption

ABSTRACT Tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis ( Mtb ), continues to pose a major global health threat, exacerbated by the emergence of drug-resistant strains and the lengthy treatment regimens required for effective management. Bedaquiline (BDQ), a key component in novel regimens for multidrug-resistant (MDR) TB, has demonstrated significant efficacy but is threatened by rising resistance. Our study investigates the potential of vitamin C to enhance BDQ’s activity and prevent resistance. We found that combining BDQ with vitamin C sterilized drug-susceptible and MDR Mtb cultures in vitro within 21 days, achieving a 6-log reduction in colony-forming units. This combination also enhanced Mtb killing in infected human macrophages and peripheral blood mononuclear cells. Transcriptomic analysis revealed that the BDQ/vitamin C combination induces widespread metabolic disruption in Mtb , characterized by upregulation of stress response and metal ion homeostasis genes and downregulation of energy metabolism and cell wall biosynthesis genes. Mechanistic studies implicated reactive oxygen species and disrupted copper homeostasis as contributing factors to the sterilization effect. These findings highlight the potential of using vitamin C as an adjunct therapy with BDQ, offering a promising strategy to enhance drug efficacy and mitigate emerging drug resistance during MDR-TB treatment. IMPORTANCE Tuberculosis (TB) remains a major global health problem, especially as drug-resistant forms become more common and harder to treat. Bedaquiline is one of the most important new drugs for treating these resistant infections, but resistance to bedaquiline is also starting to appear. This study found that the combination of vitamin C and bedaquiline sterilizes Mycobacterium tuberculosis cultures in vitro while potentiating bedaquiline activity in infected human macrophage cells. The combination appears to overwhelm the bacteria by creating stress and disrupting essential functions, like energy production and metal balance. These results suggest that vitamin C, a safe and inexpensive supplement, could be used alongside existing drugs to make treatment faster and more effective while also helping to prevent resistance.