Tuberculosis (TB) remains the leading cause of death from infectious diseases worldwide. TB drug discovery at H3D started in 2013 via funding from the Gates Foundation, which still generously supports the program along with the South African Medical Research Council (SAMRC) Strategic Health Innovation Partnerships (SHIP) initiative. Via this funding, H3D has established a medium-throughput screening platform for phenotypic and target-based screening to identify novel hits for lead generation programs, secondary in vitro assays to determine bactericidal effect of compounds as a monotherapy and in combination, and mouse infection models to assess compound in vivo efficacy. H3D’s TB medicinal chemistry team is assisted in compound design for optimizing drug-like properties of hits by in-house computational chemistry and artificial intelligence expertise. Furthermore, compound progression is supported by the H3D in vitro and in vivo drug metabolism and pharmacokinetics team through various in vitro and in vivo assays, as well as pharmacometrics modelling.
Through these in-house capabilities and active collaboration within the Tuberculosis Drug Accelerator (TBDA) consortium, H3D has established a dynamic pipeline of TB drug discovery programs. The most advanced program targets an enzyme crucial for M. tuberculosis cell wall biosynthesis, and in collaboration with the Gates Medical Research Institute (MRI), the lead molecule from the program is currently undergoing advanced toxicological studies via additional support from the IMI-ERA4TB consortium. H3D has also partnered with Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Texas A&M University, and the Molecular Mycobacteriology Research Unit (MMRU) at the University of Cape Town on two earlier-stage discovery programs. Beyond the discovery programs, H3D is also actively screening compound libraries from MMV, Calibr-Skaggs, and EU-OPENSCREEN to continuously propagate the discovery pipeline with well-validated hits for further TB drug discovery efforts.
Select H3D TB Publications:
- 1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis ACS Infect Dis. 2022, 11, 2315-2326; PMID: 36325756; doi: 10.1021/acsinfecdis.2c00392.
- Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity. J Med Chem. 2022, 9, 6903-6925; PMID: 35500229; doi: 10.1021/acs.jmedchem.2c00266.
- 1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis J. Med. Chem. 2021, 64, 12790−12807; PMID: 34414766; DOI: 10.1021/acs.jmedchem.1c00837.
- Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies. J. Med. Chem. 2021, 64, 719−740; PMID: 33395287; PMC: PMC7816196; DOI: 10.1021/acs.jmedchem.0c01727.
- Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure–Activity Relationship, Metabolism, and Biology Triaging. Journal of Medicinal Chemistry. 2021, 64, 13, 9444–9457.
For more information on our available TB assays please see here
