Pretomanid for the treatment of drug resistant pulmonary tuberculosis: a comprehensive review

Pretomanid, a novel nitroimidazoles or nitroimidazooxazines, was recently approved as part of BPaL (Bedaquiline, Pretomanid, and Linezolid) regimen for treating extensively drug-resistant (XDR) and treatment-intolerant/ nonresponsive multidrug-resistant (MDR) cases of pulmonary tuberculosis (TB). It offers new hope in the global fight against drug-resistant TB, which remains a major health challenge. However, the pursuit of better treatment outcomes has been confronted by the rapid emergence of resistance to these drugs. Resistance to pretomanid has been documented in both laboratory and clinical isolates of Mycobacterium tuberculosis. The identification of pretomanid-resistant strains of Mycobacterium tuberculosis highlights the need for judicious use, continuous surveillance and monitoring of pretomanid resistance in TB control programs to prevent further resistance development and ensure the continued success of pretomanid in treating drug-resistant TB. Although genetic mutations associated with pretomanid resistance have been identified in key genes such as ddn and fgd1 of Mycobacterium tuberculosis, the insights into the molecular mechanisms of pretomanid resistance are still quite limited. The better understanding of resistance patterns and molecular mechanisms underpinning pretomanid resistance is crucial for the establishment of uniform phenotypic DST methods and the development of molecular tools for rapid identification/ surveillance of pretomanid resistance. The present review explores the role of pretomanid in treating MDR and XDR-TB cases and provides an updated overview of the pharmacological properties, mechanisms of action, clinical efficacy, and the impact of resistance on the long-term effectiveness of pretomanid in TB treatment regimens.