Antimicrobials and Antimicrobial Resistance

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Presentation transcript:

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

Molecular Microbiology Drug Discovery & Structural Biology AMR Research @ 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

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

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

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