The SHIELD Consortium
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Transcript of The SHIELD Consortium
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