TB Drug Accelerator: Discovery Consortium Tackling Challenges to Move Hits to the Clinic

Background: In the past 50 years no new front line drugs for Mycobacterium Tuberculosis have been approved by regulatory agencies. The Bill and Melinda Gates Foundation have designed and championed a TB Drug Accelerator (TBDA) which is a groundbreaking collaboration between eight research institutions, eight pharmaceutical companies and a product development partnership to facilitate TB drug discovery.  Methods: Scientists from four continents have supplied over 2.9 million small molecules from corporate and other compound collections for screening in whole cell phenotypic assays under disease-relevant conditions. Lead identification efforts leverage the TBDA’s new research paradigm which addresses many of the bottlenecks in the way TB drugs are discovered.  Transparency, close project coordination, access to enabling expertise & capabilities, and shared optimization resources are defining attributes which facilitate the goal of generating multiple mechanistically distinct drug candidates sufficient to advance a regimen to a one month clinical proof-of-concept cure by 2024. Results: Collaborative screening has yielded 150 chemical series with whole cell tuberculosis activity. Novel assay methodologies have assisted in mapping orphan whole cell active hits to known and novel targets. Multiple series have now advanced to Lead Optimization stages of discovery and over a dozen programs are being prosecuted in the hit to lead space. Conclusions: Recent discovery efforts to identify drug candidates for TB have been hampered by the complexity of the pathogenic organism, silo’ed research teams and a lack of sharing of fundamental biology, screening and drug discovery resources. The TBDA is a novel global consortium of drug discovery companies and academic researches that are utilizing innovative scientific techniques (and some brute force) to identify and advance unique chemical matter against known and novel TB targets.