Bedaquiline resistance in tuberculosis: mechanisms, implications, and strategies to preserve efficacy

Tuberculosis (TB) remains a significant global health challenge, particularly due to its capacity to develop resistance to treatment. Once regarded as a nearly untreatable disease, TB has evolved with the emergence of multidrug-resistant TB, complicating management efforts. In response to increasing drug resistance, bedaquiline was introduced in 2012 as the first new anti-TB drug in over 50 years explicitly designed to combat multidrug-resistant TB. Bedaquiline targets mycobacterial ATP synthase, disrupting energy production and leading to bacterial cell death. However, resistance to this drug has emerged, often linked to gene mutations such as atpE and mmpR5 (Rv0678), which can reduce its effectiveness. This review explores the mechanisms driving bedaquiline resistance and its impact on TB treatment outcomes. It highlights the critical role of drug susceptibility testing in developing personalized treatment plans and emphasizes the need for enhanced surveillance, research into combination therapies, and clinical trials to address resistance. Given the growing burden of drug resistance to TB, this review aims to provide valuable insights for clinicians and public health professionals on optimizing bedaquiline use, mitigating resistance, and improving treatment success. As TB treatment strategies continue to evolve, ongoing research and vigilance are essential to preserving the efficacy of available therapies.