In 2022, the World Health Organization (WHO) recommended bedaquiline (BDQ)-based, all-oral regimens including pretomanid (Pa), linezolid (L), and moxifloxacin (M) (BPaLM), lasting 6-9 months However, BDQ-resistance is rising dramatically and threatening these advancements. Mozambique has reported BDQ resistance in 28% of MDR-TB isolates in 2024, up from 3% in 2016 and at 10% in South Africa (Ndjeka N, personal communication). Spread of BDQ-R TB must be slowed by antibiotic stewardship through more rapid, accurate, and near-patient diagnostics, and optimized management; until new treatment options with drugs that have no pre-existing resistance or are able to overcome small shifts in MIC will be available. The proposed EX-DR TB project includes diagnostic capacity strengthening, adapting treatment recommendations, and a trial of two new regimens composed of new drugs. The EDCTP EX-DR TB project will: 1. Develop treatment recommendations by a Delphi process with stakeholders - to make use of targeted next generation sequencing (tNGS) that is being rolled out by most national TB programmes - this will yield short-term benefit for patients and NTPs; and will slow the spread of BDQ-resistant bacteria; 2. Rigorously evaluate two treatment regimens composed of new drugs, in a phase 3 clinical trial conducted to the highest regulatory standard – this will be the main focus of EX-DR TB. The trial objective will be to move a regimen towards regulatory approval by FDA and/or EMA, and WHO if supported by results. Thus, EX-DR will create the tools for containing the nascent epidemic of BDQ-R TB and make them available to healthcare providers and TB Programmes. EX-DR TB will be embedded in a larger coalition of funders and partners focused on implementing and evaluating diagnostics and performing the trial beyond of the EDCTP funded area.