Medical Countermeasures for Dangerous Pathogens Dr Andrew Scott

1. Medical countermeasures for
dangerous pathogens
Andrew Scott, PhD
UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
1

2. Corporate information
‘The Defence Science and Technology Laboratory
ensures that innovative science and technology
contribute to the defence and security of the UK’
•Identify and monitor national security risks and
opportunities
•Protect the UK and our interests at home, at our border,
and internationally, in order to address physical and
electronic threats from state and non-state sources
UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
2

3. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
Portsdown West
Porton Down
Fort Halstead
Corporate information
3

4. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
Analysis CBR Systems
C4ISR
Counter Terrorism
and Security Cyber
Human Capability
Integrated
Survivability Weapons
Corporate capabilities
4

5. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
Corporate capabilities
Analysis CBR Systems
C4ISR
Counter Terrorism
and Security Cyber
Human Capability
Integrated
Survivability Weapons
‘Provides an integrated Chemistry, Biology, Radiation
and Medical Sciences capability’
CBR Division
54

6. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
CBR Division
Modelling, hazard
assessment, advice
Physical protection
Decontamination
and disposal
Detection and
diagnosisMedical
countermeasures
6

7. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
7
Biodefence pathogens
•Intra-cellular
pathogens
•More serious disease
if inhaled
•Symptoms are generic
•Insensitive to antibiotics
•Treatment is prolonged / requires
IV administration
Tularaemia
Melioidosis
Glanders
Plague
Ebola
Anthrax

8. © Crown copyright 2016 Dstl
28 September 2016
UK OFFICIAL
•Establish an in-depth knowledge of each biological agent
•Develop novel medical countermeasures active against
biological warfare (BW) agents
•Test the effectiveness of those countermeasures in the
most appropriate in vitro and in vivo models.
BW MedCM Programme
8

9. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
Microbiology group
•Containment Level 2, 3 and 4 laboratories
•Handling and manipulation of high-containment
pathogens
•Animal models of disease
9

10. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
10
Bio Medical Countermeasures Projects
BROAD
Target discovery and
early stage progression
of small molecule
MedCMs
AMIC
Engagement with
industry and evaluation
of more developed
candidate MedCMs
iMAT
Development of key
infection models and
progression of non
traditional therapies

11. Broad-spectrum antimicrobials
© Crown copyright 2016 Dstl
28 September 2016
• Conduct fundamental research into the
biology of biothreat agents
• Stimulate development of novel
antimicrobials against novel targets
• Align defence needs with public health
UK OFFICIAL 11

12. Transposon-Directed mutagenesis
– Generation of super-saturated transposon libraries
Insertion-site Sequencing
– Uses next-gen sequencing technology
– Sequence all mutants present within one experiment
• T
• I
UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
TraDIS
KanR KanR
Transposase
Random insertion
and gene tagged
Transposon
Gene B = essential
bacteria dies
Gene B = non-essential
bacteria survives
12
Transposome
complex

13. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
Moule et al. (2014) Mbio 5: e00926-13
TraDIS
• Absence of insertions
13

14. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
TraDIS
Burkholderia
pseudomallei
Yersinia
pestis
Francisella
tularensis
Yp Ft
Bp
• Conservation across other
biothreat pathogens
• Conservation across ESKAPEE
pathogens
• Identification of human
homologues
• Informatics (druggability, assay
availability, previous development)
148 targets to exploit
148
14

15. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
TraDIS for disease related targets
15
• Library of mutants
• Infection
• Recover bacteria
Gene A Gene B Gene C Gene D Gene E
Gene A Gene B Gene C Gene D Gene E
Quantitative
sequencing
Quantitative
sequencing

16. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
16
284 genes negatively
selected at 24 hours
TraDIS for disease related targets

17. Next steps…
© Crown copyright 2016 Dstl
28 September 2016
UK OFFICIAL 17
Validate relevance
in disease
Understand target function
target in the pathogen
Generate tools to support
future drug discovery efforts
Norville et al. (2011) Infect. Imm. 79, 4299-4307Custodio et al. (2016) Mol. Micro. doi: 10.1111/mmi.13531. [Epub ahead of print]

18. UK OFFICIAL© Crown copyright 2016 Dstl
28 September 2016
18
Bio Medical Countermeasures Projects
BROAD
Target discovery and
early stage progression
of small molecule
MedCMs
AMIC
Engagement with
industry and evaluation
of more developed
candidate MedCMs
iMAT
Development of key
infection models and
progression of non
traditional therapies

19. © Crown copyright 2016 Dstl
28 September 2016
UK OFFICIAL 19
Summary
Stimulating
target
development
Pulling
compounds
through