1. Antimicrobials and Antimicrobial Resistance
A Cross-Disciplinary Research Priority Area
Paul Williams – Centre for Biomolecular Sciences , School of Life Sciences, Faculty of Medicine & Health Sciences
£60 million Capital Investment
~600 Researchers
Molecular Microbiology
National Biofilm Innovation Centre
Medicinal Chemistry & Drug Discovery
Structural Biology & Biophysics

2. Molecular Microbiology Drug Discovery & Structural Biology
AMR CBS
Class II and III Pathogen Containment Laboratories
100,000 Automated Drug-Like Compound Collection
High Throughput Crystallization Robotics
Advanced & Super-Resolution Microscopy
In Vivo Infection Imaging
Research Facilities
Molecular Microbiology
Antibacterial Targets
Virulence
Quorum Sensing
Gene Regulation
Secretion
Antibacterial Drug Discovery
Synthetic & Natural Products
Repurposing Approved Agents
Bio-instructive Biomaterials
Drug Discovery & Structural Biology
Synthetic & Analytical Chemistry
Protein Crystallography
NMR, LC/MS/MS & 3D ORBI-SIMS
Structure-Guided Drug Design
High Through-Put Assay Screens
ADMET/PK/PD

3. Quorum Sensing as an Antibacterial Target
Pseudomonas aeruginosa
Staphylococcus aureus
Target Pathogens
Quorum Sensing Inhibitors (QSIs)
Quorum Sensing: Regulates virulence; Controls biofilm development; QS mutants are often avirulent in experimental animal infections
Quorum Sensing Inhibition: Attenuate Virulence; Reduce Selection for Resistance; Preserve Host Microbiota; Narrow Spectrum of Activity; Adjunct Therapy; New Diagnostics

4. Targetting Quorum Sensing in Pseudmonas aeruginosa
In silico PqsR docking- 100,000 drug-like compounds
USA FDA Approved Drugs
Isothermal Calorimetry Titration
Control
Tobramycin
Tobra+ SEN19
P. aeruginosa pqsA::lux screen
Compound Number
Hit to lead
(completed)
Medicinal Chemistry Structure Activity Relationships (SAR)
SEN019
IC50=400nM
SEN086
IC50=200nM
SEN088
IC50=129nM
SEN089
IC50=67nM
SEN015
IC50=3μM

5. High Throughput Discovery of Biofilm -Resistant Polymers for Medical Devices
Screened 1273 polymers in 20,000 assays with 4 pathogens & multiple growth conditions
Hook et al (2012) Nature Biotech 30:868
Discovered a new class of biofilm resistant polymers
Regulatory Approval for a Urinary Tract Catheter
Clinical Trials Underway in 6 UK Hospitals