Dstl Medical Countermeasures for Dangerous Pathogens

Medical countermeasures for

dangerous pathogens

Andrew Scott, PhD

UK OFFICIAL© Crown copyright 2016 Dstl

28 September 2016

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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


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Portsdown West

Porton Down

Fort Halstead

Corporate information

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28 September 2016

Analysis CBR Systems

C4ISRCounter Terrorism

and Security Cyber

Human CapabilityIntegrated

Survivability Weapons

Corporate capabilities

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28 September 2016

Corporate capabilities

Analysis CBR Systems

C4ISRCounter Terrorism

and Security Cyber

Human CapabilityIntegrated

Survivability Weapons

‘Provides an integrated Chemistry, Biology, Radiation

and Medical Sciences capability’

CBR Division

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CBR Division

Modelling, hazard

assessment, advice

Physical protection

Decontamination

and disposal

Detection and

diagnosisMedical

countermeasures

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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

http://www.isradiology.org/tropical_deseases/tmcr/chapter23/large23/23-22.jpg

http://www.isradiology.org/tropical_deseases/tmcr/chapter23/large23/23-22.jpg

© 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

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Microbiology group

•Containment Level 2, 3 and 4 laboratories

•Handling and manipulation of high-containment

pathogens

•Animal models of disease

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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

Broad-spectrum antimicrobials


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• 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

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


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TraDIS

KanR KanR

TransposaseRandom insertion

and gene tagged

TransposonGene B = essential

bacteria dies

Gene B = non-essential

bacteria survives

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Transposome

complex


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Moule et al. (2014) Mbio 5: e00926-13

TraDIS

• Absence of insertions

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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

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TraDIS for disease related targets

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• 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


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284 genes negatively

selected at 24 hours

TraDIS for disease related targets

Next steps…


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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]


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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


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UK OFFICIAL 19

Summary

Stimulating

target

development

Pulling

compounds

through

Dstl Medical Countermeasures for Dangerous Pathogens

Science

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