Grant: Foundation Grant

Antibiotic Resistance; Bacterial Pathogenesis; Macromolecular Assemblies; Membrane Proteins; Protein/Protein Interactions; Single Particle Cryoem; Structural Biology; Structure-Based Antibiotic Design; Xray Crystallography

<html> <body> <p>As underscored by the first comprehensive WHO global report (http://www.who.int/drugresistance-2014) <strong>bacterial resistance to standard antibiotic therapies is a critical health problem worldwide</strong>. The spectrum of resistant infections have increased in hospital and community settings resulting in increased mortality and health-care costs. Strains of <em>Staphylococci</em> (including the &ldquo;superbug&rdquo; <em>MRSA</em>), and members of the <em>Enterobacteriaceae</em> and <em>Pseudomonas</em> families (causing diarrhea, respiratory, urinary infections, and sepsis) are now resistant to virtually all older antibiotics. Strains of resistant <em>Mycobacterium</em> <em>tuberculosis</em> have raised a looming specter of untreatable global TB. Control of these infections requires development and prudent use of new antimicrobials, and public efforts to reduce transmission. Indeed the WHO report has invigorated a global call to arms from academic, clinical, pharmaceutical and government agencies to address the escalating health and economic burden of drug-resistant bacterial infections.<br> <br> The <strong>overarching aim of my research is the application of hybrid structural methods including x-ray crystallography, NMR, and EM coupled with application of biochemical probes <em>in vitro</em> and cellular-microbiology probes <em>in vivo</em> to perform structure/function analysis of membrane-spanning macromolecular assemblies essential to bacterial pathogenicity and antibiotic resistance</strong>. These assemblies <strong>play critical roles in bacterial cell-wall/cell-surface biogenesis</strong> and <strong>in transport of virulence proteins</strong> from bacteria to host<strong>.</strong> These roles are unique to bacteria, and generally accessible for drug/vaccine action, hallmarks of logical drug targets. My research is based on the belief and prior success that high resolution structures provide the necessary foundation for drug discovery and aims to <strong>illuminate the atomic detail, mechanism of action and specificity of the identified targets,</strong> and to exploit this information <strong>in the design of new antibiotics and vaccines</strong> to fight resistant bacterial infections.<br> <br> My group has built a strong, proven core of academic, clinical and industrial collaborations at UBC, nationally, and internationally to support our antibiotic discovery research. These include in the areas of <strong>microbiology</strong> (giving access to microbial genetics, virulence assays, mouse models), <strong>biophysics/computational biology</strong> (mass spec, EM and molecular modeling), and <strong>medicinal chemistry</strong> (providing expertise in a variety of chemical scaffolds and screening libraries). Access to infrastructure/resources comes through my association: locally with the CFI funded biophysics initiative Adv. Struct. Research in Infectious Disease (ASTRID), Center for TB Research and Center for Drug Research and Discovery (CDRD); and through my HHMI affiliation, with access to state-of-the-art xray and cryoEM data collection. My research is enriched by participation in the Can-UK consortium on Cell-wall research, the JPIAMR EU-Canada initiative on antibiotic resistance, and the new NCE GlycoNet, all collectively providing cross fertilization via timely scientific connections, sharing of methods and reagents as well as cross-training of students and PDFs. I believe that the multi-disciplinary nature of my research provides a proven, flexible foundation of training in structural biology, biochemistry, cellular microbiology and drug discovery for the students and fellows under my supervision, paving the way for career paths in academia, industry and the public sector.</p> </body> </html>