Our lab is studying the structure of proteins and other biomolecules that play a role in bacterial infection. Our goal is to use this information to develop new compounds that can either counteract antibiotic resistance or create new antibiotics by targeting essential structures that are crucial for the survival and pathogenicity of bacteria.
The threat of antibiotic resistance
Antimicrobial resistance is projected to cause more annual deaths than cancer by 2050, yet the clinical pipeline for new antibiotics remains sparse. As pathogenetic bacteria acquire various strategies to evade antibiotic action, previously treatable infections increasingly result in therapeutic failure.
Our lab employs a structure-guided approach to investigate the mechanisms underlying microbial pathogenesis and drug resistance. By integrating X-ray crystallography, cryo-electron microscopy, and other biophysical techniques, we resolve high-resolution structures of key protein targets, including antibiotic resistance enzymes, protein secretion systems underlying pathogenicity, and a range of pathogen specific virulence factors. These insights reveal the atomic blueprints, mode of action, inherent dynamic motions and, collectively, potential mechanistic vulnerabilities we can exploit for the design of next-generation antimicrobials and vaccines.
Combatting beta-lactam resistance
We focus on preserving the efficacy of beta-lactam antibiotics such as penicillins and cephalosporins by investigating the atomic and mechanistic details of resistance mechanisms of pathogenic superbugs such as Methicillin Resistant Staphylococcus aureus (MRSA), Enterobacteriaceae and other drug resistant bacteria of the World Health Organization designated ESKAPEE cohort. This molecular information has helped guide development of novel antibacterials and vaccines in collaboration with academic and industry partners.
Bacterial secretion systems as virulence therapeutic targets
Many pathogenic bacteria use complex multi membrane spanning nanomachines to inject specific bacterial virulence proteins into host cells in a process essential for subsequent disease. Our lab has utilized a hybrid approach of single particle cryo electron microscopy and in-situ cryo electron tomography, coupled with information from X-ray crystallography, NMR, mass spectrometry and cellular microbiology. For example, we have mapped the atomic structures of the 3MDa multicomponent, triple membrane spanning Type III secretion system (T3SS) in both Salmonella typhimurium and enteropathogenic Escherichia coli.
Structure guided understanding and inhibition of bacterial cell wall biogenesis in pathogenic bacteria
Bacterial survival within their particular environmental niches depends on an intricately assembled protective cell wall that can adapt during changes in cell rest, growth, division, sporulation and infection. The complex molecular protein machinery underlying cell wall synthesis and modification are important potential targets for new antibiotics, but has remained underexplored due to the complex substrates, membrane associated nature and variable partnering of the enzymes involved . Our lab investigates this multi-enzyme cell wall "nanomachine" to uncover new vulnerabilities that can be exploited for novel antibiotics.
Integrated structural biology for immune evasion and therapeutic discovery
We investigate how pathogens, including Staphylococcus bacteria and SARS-CoV-2 viruses, evade immune surveillance through glycosylation and surface protein modifications, and work to identify novel therapeutic strategies that block these immune escape pathways.
Techniques and facilities
Our lab combines expertise and infrastructure for cutting-edge cryo-electron microscopy (single particle cryo-EM and cryo electron tomography), with Dr. Strynadka leading UBC’s High-Resolution Macromolecular Electron Microscopy (HRMEM) facility as well as X-ray crystallography and small angle X-ray scattering. We are additionally equipped with a state-of-the-art biophysical suite, alongside a range of protein expression and purification systems, high-throughput crystallization robotics, and assay development capabilities.