Thomas Dick; Paris, 19 September 2016 WGND Workshop Progress Updates on Global TB Drug Discovery and Preclinical Activities Thomas Dick; Paris, 19 September 2016
Bench to Bedside Translational Research in TB The program (founded in 2014) Bench to Bedside Translational Research in TB Theme 1: Target Discovery Theme 2: Drug Development Theme 3: Clinical Trials Theme 4: Treatment Delivery Lead: A/Prof. Thomas Dick NUS Microbiology & Immunology Lead: Prof. Alex Matter A*STAR Experimental Therapeutics Centre Lead: Prof. Nick Paton NUS Medicine Lead: A/Prof. Mishal Khan NUS School of Public Health
The people (annual meeting 2015)
Infrastructures
Bench to Bedside Translational Research in TB Today SPRINT-TB RESEARCH Bench to Bedside Translational Research in TB Theme 1: Target Discovery Theme 2: Drug Development Theme 3: Clinical Trials Theme 4: Treatment Delivery Lead: A/Prof. Thomas Dick NUS Microbiology & Immunology Lead: Prof. Alex Matter A*STAR Experimental Therapeutics Centre Lead: Prof. Nick Paton NUS Medicine Lead: A/Prof. Mishal Khan NUS School of Public Health
SPRINT-TB target & lead finding: Approaches, projects, portfolio
Back to targets Forget targets The future Themes Gengenbacher 2015 Chemistry and Biology 22,5 Gopal 2015 Current Opinion Microbiology 21, 7 Kana 2014 Tuberculosis 94, 551
Back to targets Clinically validated anti-persister targets De novo targets: target-based whole-cell; from anti-cancer to anti-TB
Clinically validated anti-persister targets: Bedaquiline targets epsilon subunit of ATP synthase Kundu 2016. Agents Chemotherapy, doi: 10.1128/AAC.01291-16 Hotra 2016 The FEBS Journal doi:10.1111/febs.13715.
Clinically validated anti-persister targets: Pyrazinamide targets CoA and PDIM synthesis Via 2015 ACS Infectious Diseases 1, 203 Gopal 2016 ACS Infectious Diseases, doi: 10.1021/acsinfecdis.6b00070. Gopal 2016 in preparation Yee 2016 in preparation
Chemistry (cap, P1, P2, warhead) De novo targets: target-based whole-cell; from anti-cancer to anti-TB: Caseinolytic protease and bortezomib Proof of concept compound Clp IC50 = 1.5 uM MIC50 = 3 uM Proteasome IC50 = 0.4 80 fold less active on proteasome Bortezomib Clp IC50 = 6 uM MIC50 = 6 uM Proteasome IC50 = 0.005 Chemistry (cap, P1, P2, warhead) Clp assay Proteasome assay Growth inhibition Moreira 2015 mBio 6, e00253-15 Moreira 2016 submitted
Back to targets Clinically validated anti-persister targets: ATP synthase epsilon, PanD & Mas/Pps De novo targets: target-based whole-cell; from anti-cancer to anti-TB Caseinolytic protease
Forget targets Membrane corruption as anti-persistence & anti-resistance strategy Dirty and reactive is good
Membrane corruption as anti-persistence & anti-resistance strategy Alkylindoles Xanthones Boromycin MIC50 Mtb = 2 MIC50 Mav = 2 MIC50 Mab = 19 MIC50 Mtb = 2 MIC50 Mav = 2 MIC50 Mab = 7 MIC50 Mtb = 0.05 MIC50 Mav = 0.02 MIC50 Mab = >5 Moreira 2016 Frontiers in Microbiology doi.org/10.3389/fmicb.2016.00199. Mukherjee 2016 Future Microbiology doi: 10.2217/fmb-2015-0015 Koh 2016 European Journal of Medicinal Chemistry, doi:10.1016/ejmech.2016.07.068
Dirty and reactive is good: whole cell active fragments Gopal 2014 Current Opinion Micro 21, 7 Moreira 2016 Frontiers Microbiology, doi: 10.3389/fmicb.2016.01392 Negatu 2016 in preparation
Forget targets Membrane corruption as anti-persistence & anti-resistance strategy Boromycin, xanthones, alkylindoles Dirty and reactive is good 76 new anti-TB fragment hits
The future 1 back to targets & forget targets, ..with new approaches, new chemotherapeutic strategies 2 new drug development strategy and more biology
Curing TB and NTM disease – broad spectrum antimycobacterials Mtb 76 Mav 62 Mab 43 TB fragment (rule of 3) hits TB drug-like (rule of 5) hits Moreira 2016 Frontiers Microbiology, doi: 10.3389/fmicb.2016.01392 Negatu 2016 in preparation Aziz & Low 2016 in preparation Wu 2016 in preparation
NTM biology - not only biofilms: extremely resistant spore-like mini cells Wu 2016 Frontiers in Microbiology, doi: 10.3389/fmicb.2016.00947 Wu 2016 BMC Genomics, under revision. Wu 2016 Frontiers in Microbiology, doi: 10.3389/fmicb.2016.01390. Wu 2015 AAC 59, 7786 Wu 2015 Future Microbiology 10, 449
SPRINT-TB target & lead finding: Approaches, projects, portfolio Back to targets Clinically validated anti-persister targets De novo targets: target-based whole-cell; from anti-cancer to anti-TB Forget targets Membrane* corruption as anti-persistence & anti-resistance strategy Dirty and reactive** is good The future Curing TB and NTM disease - broad spectrum antimycobacterials NTM biology: not only biofilms, extremely resistant spore-like mini cells *crazy **unacceptable
The lab
Posters
F r i e n d s F u d e r s NUS MED BLS3 Core Team
Registration now open at Visit us 2nd Annual Symposium November 11, 2016 Registration now open at www.tuberculosis.sg
Michelle Yee
SPRINT-TB PROJECTS - Funding source Theme 1: Target Discovery Theme 2: SINGAPORE PROGRAMME OF RESEARCH INVESTIGATING NEW APPROACHES TO TREATMENT OF TUBERCULOSIS SPRINT-TB PROJECTS Theme 1: Target Discovery Theme 2: Drug Discovery Theme 3: Clinical Development Theme 4: Treatment Delivery NMRC TCR Flagship UK MRC Others Dormancy Boromycin Whole Cell Screen PET Ligands TRUNCATE-TB TB Research in Cambodia Celecoxib WBA Celecoxib Trial Xanthones Bortezomib Resistance Bortezomib Chemistry APEC Pyrazinoic Acid/PZA Fragments PET/MRI Clinical Studies A-TRACTION Network Microeconomic evaluation Preclinical Studies TB Animal Models NMRC CS-IRG GSK NMRC CG NMRC B&B* Gender, barriers & Incentives Analysis Pascolizumab Trial NMRC CBRG FRP NMRC CSA Faropenem EBA & WBA NUS Aspiration ATP Synthase Indoles for TB mTB Genomic Database NMRC CBRG NUS Seeds NUS Start-up NHIC Clp Screen Rifampicin WBA MIST TB Imaging **** WBA Contacts Study Bortezomib WBA Sputum Study - Funding source NUH Pitch FMUI-SoM