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