Presentation - Working Group for New TB Drugs

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Transcript Presentation - Working Group for New TB Drugs

WGND Workshop
Progress Updates on Global TB Drug Discovery and
Preclinical Activities
Thomas Dick; Paris, 19 September 2016
The program (founded in 2014)
Bench to Bedside Translational Research in TB
Theme 1:
Theme 2:
Theme 3:
Theme 4:
Target
Discovery
Drug
Development
Clinical
Trials
Treatment
Delivery
Lead:
A/Prof. Thomas Dick
Lead:
Prof. Alex Matter
Lead:
Prof. Nick Paton
Lead:
A/Prof. Mishal Khan
NUS Microbiology & Immunology
A*STAR Experimental Therapeutics
Centre
NUS Medicine
NUS School of Public Health
The people (annual meeting 2015)
Infrastructures
Today
SPRINT-TB RESEARCH
Bench to Bedside Translational Research in TB
Theme 1:
Theme 2:
Theme 3:
Theme 4:
Target
Discovery
Drug
Development
Clinical
Trials
Treatment
Delivery
Lead:
A/Prof. Thomas Dick
Lead:
Prof. Alex Matter
Lead:
Prof. Nick Paton
Lead:
A/Prof. Mishal Khan
NUS Microbiology & Immunology
A*STAR Experimental Therapeutics
Centre
NUS Medicine
NUS School of Public Health
SPRINT-TB target & lead finding:
Approaches, projects, portfolio
Themes
Back to targets
Forget targets
The future
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
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
Chemistry
(cap, P1, P2, warhead)
Clp IC50 = 6 uM
MIC50 = 6 uM
Proteasome IC50 = 0.005
Clp assay
Moreira 2015 mBio 6, e00253-15
Moreira 2016 submitted
Proteasome
assay
Growth inhibition
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
Boromycin
MIC50 Mtb = 0.05
MIC50 Mav = 0.02
MIC50 Mab = >5
Xanthones
MIC50 Mtb = 2
MIC50 Mav = 2
MIC50 Mab = 7
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
Alkylindoles
MIC50 Mtb = 2
MIC50 Mav = 2
MIC50 Mab = 19
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
Moreira 2016 Frontiers Microbiology, doi: 10.3389/fmicb.2016.01392
Negatu 2016 in preparation
Aziz & Low 2016 in preparation
Wu 2016 in preparation
TB drug-like (rule of 5) hits
NTM biology - not only biofilms: extremely resistant sporelike 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
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F
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NUS MED BLS3 Core Team
Visit us
2nd Annual Symposium
November 11, 2016
Registration now open at
www.tuberculosis.sg
Michelle Yee
SINGAPORE PROGRAMME OF RESEARCH INVESTIGATING
NEW APPROACHES TO TREATMENT OF TUBERCULOSIS
SPRINT-TB PROJECTS
Theme 1:
Theme 2:
Target Discovery
Drug Discovery
Theme 3:
Clinical
Development
UK MRC
NMRC TCR Flagship
TRUNCATE-TB
Dormancy Boromycin
Whole Cell Screen PET Ligands
Celecoxib WBA
Xanthones Bortezomib Resistance Bortezomib
Celecoxib Trial
APEC
Chemistry
Fragment
Pyrazinoic Acid/PZA
PET/MRI Clinical Studies A-TRACTION Network
s
Preclinical Studies TB Animal Models
GSK
NMRC CS-IRG
NMRC CG
NMRC B&B*
Pascolizumab Trial
NMRC
CBRG
FRP
ATP
Synthase
Indoles for TB
NMRC CBRG
Clp
Screen
- Funding source
NMRC CSA
Faropenem EBA &
WBA
NUS Seeds
NUS Start-up
Rifampicin
**** WBA TB Imaging Contacts
WBA
Study
Bortezomib
Sputum
WBA
Study
NUH Pitch
FMUI-SoM
Theme 4:
Treatment
Delivery
Others
TB Research in
Cambodia
Microeconomic
evaluation
Gender, barriers &
Incentives Analysis
NUS Aspiration
mTB Genomic
Database
NHIC
MIST