The SHIELD consortium
David Dockrell
University of Sheffield
Universities of SHeffield, BIrmingham, Edinburgh, and NewcastLe Led Partnership to
Develop Host Defence Therapeutics
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
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
• Bottlenecks involve microbicidal responses; -killing capacity - calibration of microbicidal responses
Healthy
Co-morbidity
Multidisciplinary team
• Microbiology and Immunology• Chemistry; probes and compounds• Physics; optical imaging• Clinicians; patients and phase I trials
experience• Bioinformatic and Statistical• Industry partners
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
Environment
Bateson (CDBG); Zebrafish facility
Imagine optical imaging
OPTIMA
Bacteria and microscopy Models Translation
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
Phagolysosome
MitochondriaCathepsin D
aaBcl2? proApo(BH3)
Cytochrome C,Smac, DIABLOrelease
aCaspase
Mechanisms of Mf apoptosis
bacterium
bacterium mROS
Repurposing for engagement
Similarly for clodronate
Synthetic targets
03/05/2023
Hydroxychloroquine analogues – structure activity studies to determine viable labelling sites
NCl
HNOH
NCl
HNN
OH
NCl
HNNH2
NCl
HNN
NH2
NCl
N
HN
NCl
HNOH
NCl
HN
Screens
A Scree format with Spectrum collection, B Inflammation screen 2,000 compounds,C S. aureus killing 660 compounds
Validation platform
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
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