Treatment optimization through pharmacokinetic evaluation is needed to improve outcomes in tuberculous meningitis (TBM). Clinical assessment of drug penetration into the central nervous system (CNS) is limited to cerebrospinal fluid (CSF) sampling, which may not reflect drug exposures at the site-of-disease. We characterized the pharmacokinetics of antituberculosis drugs in CNS…
Developing tuberculosis drug regimens requires coordinated discovery of multiple, mechanistically distinct agents, which challenge traditional single-asset models. The Tuberculosis Drug Accelerator (TBDA) was established as a multi-organizational consortium to enable collaborative discovery across academia, industry and research institutions. Over more than a decade, the TBDA has demonstrated how such collaborations…
Alveolar macrophages are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this pathogen, allowing Mtb to persist and replicate. Interstitial macrophages (IMs) are enlisted to restrict bacterial growth and limit immune evasion. While IMs have been implicated in controlling acute…
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and defined by formation of granulomas, immune aggregates that can restrict or support bacterial replication. Macrophages are fundamental components of granulomas and TB pathogenesis, yet their population structure and functional diversity is incompletely understood. The interaction between macrophages and Mtb in…
Strain diversity in (Mtb) underlies distinct clinical presentations and outcomes, but the range of drug susceptibility phenotypes among clinical isolates is poorly understood. We aimed to identify drug response patterns in phylogenetically diverse clinical isolates to combination treatment. We selected 13 strains out of 641 drug-sensitive clinical isolates that capture…
The bedaquiline, pretomanid, and linezolid (BPaL) regimen has shown significant efficacy in treating patients with multidrug-resistant and extensively drug-resistant tuberculosis. This study assessed whether delamanid, a closely related nitroimidazole, could replace pretomanid in the BPaL regimen by directly comparing the efficacy of bedaquiline, delamanid, and linezolid (BDL) and BPaL regimens…
Tuberculosis (TB) chemotherapy was once considered a crowning triumph of modern medicine but has since reemerged as a persisting paradox. While therapeutically still effective in most cases, current frontline treatments for TB remain largely unchanged from their introduction over 50 years ago and continue to require a minimum of 6…
Despite the approval of two first-in-class anti-tuberculars over the past two decades, the global burden of tuberculosis (TB) remains unacceptably high, in part due to the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). This review summarizes advances and ongoing challenges in anti-TB drug discovery, focusing on identifying…
