Identification of High-Quality Hits for Tuberculosis (HIT-TB) was a collaborative project between the National Institute of Allergy and Infectious Diseases (NIAID) and academic institutions in the United Kingdom and South Africa. It focused on combating tuberculosis, which infects approximately one-third of the world’s population and is becoming increasingly resistant to existing drugs. The goal of HIT-TB was to identify a series of small molecules that inhibited growth of Mycobacterium tuberculosis under a variety of in vivo relevant conditions. The elucidation of the mechanism of action of these inhibitors would lead to the identification of target-inhibitor couples that would serve as promising leads in drug discovery with the potential to develop novel regimens to treat TB. The program sought to combine the power of high-throughput screening with chemically diverse small molecule libraries and target-based approaches to identify small molecules and druggable targets with the potential to accelerate clinically meaningful treatments against TB.
- Production of high-quality chemical hit series that engage potentially novel targets by scaling up the tools of high-throughput whole cell-based techniques using multiple libraries of diverse, high-quality molecules that efficiently sample chemical diversity.
- Development of hit prioritization strategies would enable rapid identification of the most promising hit series for target identification.
- National Institute of Allergy and Infectious Diseases (NIAID)
- Bill & Melinda Gates Foundation*
- University of Cambridge
- University of Cape Town
- University of Dundee
*Provided financial or in-kind support for this program.
Susan Wiener, Senior Project Manager, [email protected]
Results & Accomplishments
Validating Small Molecule Libraries
Screened and validated new small molecule libraries containing more than 1.6 million compounds from more than 10 commercial and academic libraries.
Identifying Molecules to Engage Novel Targets
Generated sufficient structure-activity relationships (SARs) to establish quality of hit series and applied a hit prioritization strategy that enabled selection of scaffolds (core structures) inhibiting novel TB targets.
Identifying Vulnerable TB Targets
Identified vulnerable TB targets; began developing potent inhibitors of several enzymes in the well-validated CoA pathway and constructing genetically modulated strains with titratable expression of essential CoA enzymes for screening.
Enriching and Disseminating Screening Libraries
Enriched screening libraries and results of screening using computational predictions: used informatics tools, including databases and modeling software, together with data arising from whole-cell screening and structure-based fragment drug discovery, to enhance the linkage between protein structural databases designed for TB and chemical databases designed for drug discovery. Updated Toccata and Chopin (Mtb proteome sequence and structure databases) and made them available to collaborators.
Identifying Targets of Quality Hit Series
Developed a hit triage strategy to prioritize compounds across diverse conditions, which assisted other members of the Gates Foundation-supported TB Drug Accelerator enterprise. At the conclusion of the project, all promising series were placed on hold at various stages of formal hit assessment, hit-to-lead, or lead optimization stages and transitioned to the SHORTEN-TB project.
The leading candidate (MMV46) was transitioned into the SHORTEN-TB project with the remaining hurdle being the identification of a metabolically stable yet potent anti-tubercular compound with sufficient in vivo exposure based on ADME optimization to warrant marmoset efficacy evaluation.