Vilchèze Catherine, Rajagopalan Saranathan, Kalluru Raja Sab, Banaei Niaz, Jacobs William R
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
mBio. 2025 Jun 25:e0148425. doi: 10.1128/mbio.01484-25.
Tuberculosis (TB), a disease caused by the bacterium (), 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 cultures within 21 days, achieving a 6-log reduction in colony-forming units. This combination also enhanced killing in infected human macrophages and peripheral blood mononuclear cells. Transcriptomic analysis revealed that the BDQ/vitamin C combination induces widespread metabolic disruption in , 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.
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 cultures 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.
结核病（TB）是由结核分枝杆菌引起的一种疾病，仍然是全球主要的健康威胁，耐药菌株的出现以及有效管理所需的漫长治疗方案使其问题更加严重。贝达喹啉（BDQ）是耐多药（MDR）结核病新治疗方案的关键组成部分，已显示出显著疗效，但面临耐药性上升的威胁。我们的研究调查了维生素C增强BDQ活性并预防耐药性的潜力。我们发现，将BDQ与维生素C联合使用可在21天内使药物敏感和MDR结核分枝杆菌培养物灭菌，使菌落形成单位减少6个对数。这种联合还增强了在受感染的人类巨噬细胞和外周血单核细胞中的杀菌作用。转录组分析表明，BDQ/维生素C联合使用会在结核分枝杆菌中引起广泛的代谢紊乱，其特征是应激反应和金属离子稳态基因上调，能量代谢和细胞壁生物合成基因下调。机制研究表明活性氧和铜稳态破坏是杀菌效果的促成因素。这些发现突出了将维生素C作为BDQ辅助治疗的潜力，为在MDR-TB治疗期间提高药物疗效和减轻新出现的耐药性提供了一种有前景的策略。
结核病仍然是一个主要的全球健康问题，尤其是耐药形式变得更加普遍且更难治疗。贝达喹啉是治疗这些耐药感染最重要的新药之一，但对贝达喹啉的耐药性也开始出现。这项研究发现，维生素C和贝达喹啉联合使用可使结核分枝杆菌培养物灭菌，同时增强贝达喹啉在受感染的人类巨噬细胞中的活性。这种联合似乎通过产生应激和破坏诸如能量产生和金属平衡等基本功能来压倒细菌。这些结果表明，维生素C作为一种安全且廉价的补充剂，可以与现有药物一起使用，使治疗更快、更有效，同时有助于预防耐药性。
