Structural Basis of Broad-Spectrum β-Lactam Resistance in Staphylococcus aureus
This week we profile a recent publication in Nature from first authors Andrew Alexander (pictured, far left back row) and Liam Worrall ( third from left, back row), co-authors Jinhong Hu (inset, top), Marija Vuckovic (fourth from left, back row), Solmaz Sobhanifar (inset, bottom), Claire Atkinson, manager of the High Resolution Macromolecular Electron Microscope Facility at UBC (front, far right), and Principal Investigator Natalie Strynadka (seated).
Can you provide a brief overview of your lab’s current research focus?
Our laboratory’s research focuses on atomic resolution characterization and analysis of microbial targets, often membrane protein assemblies, that mediate drug resistance or are potential new targets for structure-guided antibiotic design.
What is the significance of the findings in this publication?
We have used cryogenic electron microscopy to characterize the first atomic structures of a novel receptor that senses beta-lactam antibiotics in the environment, then signals through the membrane to control (via unprecedented direct proteolysis of a repressor), expression of genes underlying broad spectrum beta-lactam antibiotic resistance in drug resistant Staph aureus strains. Staphylococcal aureus is one of the most notorious of the drug resistant clinical and community pathogens, with strains such as MRSA widely disseminated globally, and a leading cause of nosocomial (hospital acquired) infections. Staph aureus drug resistant infections are a top concern of the WHO with new strategies to overcome drug resistance direly needed. Beta-lactams are still the most widely used, effective and economical of the antibiotic classes, and their preservation again resistance mechanisms through cocktail therapies continues to be an ongoing major avenue of new therapeutic development.
What are the next steps for this research?
This receptor and the atomic and functional understanding gleaned from our work represents a critical new avenue of intervention to block beta-lactam antibiotic resistance in Staph aureus and potentially other drug resistant global pathogens including M.Tb and C. difficile that have analogous receptors. These first atomic coordinates and mechanistic insights can be used to efficiently drive structure guided development of new therapeutics targeting this receptor.
If you’d like to mention your funding sources, please list them.
We are grateful to the Canadian Foundation of Innovation, BC Knowledge Development Fund and Canadian Institutes of Health Research for infrastructure and operational funding of this research.