Theme 2: Drug Development
Theme 2 builds on targets uncovered by Theme 1 and drives them through lead finding and optimisation programmes. The team runs high-throughput screening, medicinal chemistry and pharmacology to advance leads through optimisation and preclinical development, producing new tuberculosis drug candidates ready for clinical testing. The theme also creates imaging biomarkers that can signal early drug or regimen activity against dormant TB bacilli, and it develops TB animal models together with the preclinical studies needed to support investigational product use in humans.
Theme 2 Lead: Prof. Alex Matter, Experimental Therapeutics Centre (ETC), Agency for Science, Technology and Research (A*STAR), Singapore.
Projects
Novel inhibitor of mycobacterial transporter MmpL3
Project lead: Annanya Shetty
A high-throughput screen of roughly 72,000 compounds returned 16 hits that blocked growth of Mycobacterium bovis BCG. Among them, a novel acetamide, E11, was selected for priority follow-up because it induced the cell envelope stress responsive promotor piniBAC, showed potent cidal activity against both growing and non-growing M. tuberculosis, had low cytotoxic and hemolytic activity, and displayed a dynamic structure activity relationship. Resistant mutant selection and whole genome sequencing pointed to the mycolic acid transporter (Mycobacterial Membrane Protein Large) MmpL3 as a candidate target of the hit. Biochemical analyses with mycobacterial spheroplasts indicate that E11 does inhibit translocation of trehalose monomycolate (TMM) and the subsequent synthesis of trehalose dimycolate (TDM). Given the widely reviewed therapeutic potential of MmpL3, this novel scaffold offers an anti-mycobacterial lead with attractive potency and selectivity for optimisation.
Selected publication: Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption. Front Microbiol. 2018 Dec 4;9:2960.
Read the publicationNovel PET Tracers for mABs: TB Imaging
Project lead: Dr. Claire Naftalin
This project is developing new PET tracers for imaging pulmonary TB, built on labelled monoclonal antibodies (initially antibodies against tumour necrosis factor-α). TNF-α is a key cytokine in both the immune response to TB and the inflammatory response and clinical symptoms of the disease. The immuno-PET approach uses tracer doses of labelled anti-TNF-α to quantify and localise where TNF-α is secreted. The method will later be extended to label other monoclonal antibodies for TB imaging.
TB Animal Model Platform
Project lead: Dr. Rupangi Verma
This project seeks a better approach to TB animal models that helps prioritise regimens for clinical trials. It tests a range of mouse TB relapse models, both established and several potential new ones, and refines them further so relapse rates match those observed in TB clinical trials. PET-based imaging of mice is also incorporated so animals can be followed for relapse over time, mirroring clinical trial practice more closely than the usual method of randomly sacrificing animals to check for TB relapse.
Back to Research ThemesTheme 2 Collaborators
- Institute of Molecular & Cell Biology, A*STAR, Singapore — Chen Qingfeng
- Singapore Bioimaging Consortium, A*STAR, Singapore — Edward Robins, Julian Goggi, Kishore Bhakoo
- Comparative Medicine, National University of Singapore, Singapore — Peter Cullen
- Public Health Research Institute, New Jersey, USA — Veronique Dartois
Facilities and Expertise
Central to Theme 2, the Experimental Therapeutics Centre (A*STAR) provides industry standard drug discovery facilities and expertise for lead finding and optimisation, delivering TB drug candidates for clinical development. Theme 2 research also draws on the National University of Singapore's BSL-3 animal facility and the A*STAR-NUS Clinical Imaging Research Centre (CIRC), whose state-of-the-art tools, such as PET/MRI, enable fundamental advances in TB imaging.
BSL-3 lab animal facility at National University of Singapore.
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Partner links: Experimental Therapeutics Centre Management · Institute of Molecular & Cell Biology · Singapore Bioimaging Consortium · Public Health Research Institute