1. Thomas Dick; Paris, 19 September 2016
WGND Workshop
Progress Updates on Global TB Drug Discovery and Preclinical Activities
Thomas Dick; Paris, 19 September 2016

2. 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

3. The people (annual meeting 2015)

4. Infrastructures

5. 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

6. SPRINT-TB target & lead finding:
Approaches, projects, portfolio

7. 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

8. Back to targets Clinically validated anti-persister targets
De novo targets: target-based whole-cell;
from anti-cancer to anti-TB

9. Clinically validated anti-persister targets: Bedaquiline targets epsilon subunit of ATP synthase
Kundu Agents Chemotherapy, doi: /AAC
Hotra 2016 The FEBS Journal doi: /febs

10. Clinically validated anti-persister targets: Pyrazinamide targets CoA and PDIM synthesis
Via 2015 ACS Infectious Diseases 1, 203
Gopal 2016 ACS Infectious Diseases, doi: /acsinfecdis.6b00070.
Gopal 2016 in preparation
Yee 2016 in preparation

11. 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, e
Moreira 2016 submitted

12. 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

13. Forget targets
Membrane corruption as anti-persistence & anti-resistance strategy
Dirty and reactive is good

14. 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 Frontiers in Microbiology doi.org/ /fmicb
Mukherjee 2016 Future Microbiology doi: /fmb
Koh 2016 European Journal of Medicinal Chemistry, doi: /ejmech

15. Dirty and reactive is good: whole cell active fragments
Gopal 2014 Current Opinion Micro 21, 7
Moreira 2016 Frontiers Microbiology, doi: /fmicb
Negatu 2016 in preparation

16. Forget targets
Membrane corruption as anti-persistence & anti-resistance strategy
Boromycin, xanthones, alkylindoles
Dirty and reactive is good
76 new anti-TB fragment hits

17. The future 1 back to targets & forget targets,
..with new approaches, new chemotherapeutic
strategies
2 new drug development strategy
and more biology

18. 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: /fmicb
Negatu 2016 in preparation
Aziz & Low 2016 in preparation
Wu 2016 in preparation

19. NTM biology - not only biofilms: extremely resistant spore-like mini cells
Wu 2016 Frontiers in Microbiology, doi: /fmicb
Wu 2016 BMC Genomics, under revision.
Wu 2016 Frontiers in Microbiology, doi: /fmicb
Wu 2015 AAC 59, 7786
Wu 2015 Future Microbiology 10, 449

20. 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

21. The lab

22. Posters

23. F r i e n d s F u d e r s
NUS MED BLS3 Core Team

24. Registration now open at
Visit us
2nd Annual Symposium
November 11, 2016
Registration now open at

25. Michelle Yee

26. 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