The SHIELD consortium is a partnership between 4 UK universities to develop host defence therapeutics. It aims to enhance macrophage microbicidal mechanisms, alter the negative consequences of excessive neutrophil responses while preserving antibacterial function, and measure pathogen adaptation. The multidisciplinary team will pursue this through probes, compounds, imaging, and clinical trials experience. Industry partners will help with the academic-industry interface to translate findings.

1. The SHIELD consortium
David Dockrell
University of Sheffield

2. Universities of SHeffield, BIrmingham,
Edinburgh, and NewcastLe Led Partnership to
Develop Host Defence Therapeutics

3. The real life face of AMR
• 42 yo taken ill with
pneumonia while on
holiday
• Diagnosed with acute
leukemia
• Infected with an MDR
bacterium, needs
allogeneic heamatopoeitic
stem cell transplant

4. The host response often determines the outcome of
infectious disease not the success of antimicrobial killing
• Many common bacterial
pathogens owe their success to
exploiting niches in the immune
response
• Susceptibility is poorly defined
– but can be linked to common
patient characteristics e.g. age,
medical co-morbidity
• Mortality often occurs despite
effective pathogen clearance

5. • Bottlenecks involve microbicidal responses;
-killing capacity
- calibration of microbicidal responses
Healthy
Co-morbidity

6. Multidisciplinary team
• Microbiology and Immunology
• Chemistry; probes and compounds
• Physics; optical imaging
• Clinicians; patients and phase I trials
experience
• Bioinformatic and Statistical
• Industry partners

7. Academic Industry Interface
• Academic
– Dockrell, Renshaw, Marriott, Condliffe, Foster,
Hobbs, Jones, Sabroe, Mitchell
– Whyte, Fitzgerald,Dahliwal, Bradley, Baillie, Rossi,
Walmsley, Brown, Hume, Haslett, Simpson,
Haniffa
• Industry
– RedX, Sygnature, Medimmune, Pfizer, Astra
Zeneca, GSK

8. Environment
Bateson (CDBG); Zebrafish facility
Imagine optical imaging
OPTIMA
Bacteria and microscopy Models Translation

9. Aims
• Enhance macrophage microbicidal
mechanisms
• Alter the negative consequences of excessive
microbicidal generation by neutrophils, while
preserving antibacterial responses.
• Measure pathogen adaptation to immune
selective pressure
• Establish the therapeutic potential and in vivo
efficacy in patients at risk of infection

10. Phagolysosome
MitochondriaCathepsin D
aaBcl2? proApo
(BH3)
Cytochrome C,
Smac, DIABLO
release
aCaspase
Mechanisms of Mf apoptosis
bacterium
bacterium mROS

11. Repurposing for engagement
Similarly for clodronate

12. Synthetic targets
28/09/2016
Hydroxychloroquine analogues – structure activity studies to determine viable
labelling sites

13. Screens
A Scree format with Spectrum collection, B Inflammation screen 2,000 compounds,
C S. aureus killing 660 compounds

14. Validation platform

15. Timeline 2016-2021
• Feb 2017-2021
– 2018 Identify initial screens
– 2019 Identification of initial targets
– 2020 Selection of lead compounds for hit
optimization
– 2021 Plan Phase I trial