Structural Insight into the Staphylococcus aureus ATP-Driven Exporter of Virulent Peptide Toxins
This week we profile a recent publication in Science Advances from Natalie Zeytuni (pictured, front, third
from right), Jinhong Hu (front, right) and Liam Worrall (back row, third from right) in the laboratory of
Dr. Natalie Strynadka (front, left) at the Department of Biochemistry and Centre for Blood Research at UBC.
Can you provide a brief overview of your lab’s current research focus?
In the Strynadka lab, our primary focus is to address the growing threat of antibiotic resistance through the structure-based design of inhibitors that either block existing antibiotic resistance mechanisms, or provide novel therapies by targeting proteins and macromolecular assemblies essential to bacterial viability or pathogenesis.
What is the significance of the findings in this publication?
Methicillin-resistant Staphylococcus aureus (MRSA) are resistant to beta-lactam antibiotics and present a major health challenge in both hospital- and community-acquired infections. Staphylococcal infections are mediated by a large array of secreted toxins including the phenol-soluble modulins (PSMs), short alpha-helical peptides with key roles in pathogenesis. PSMs are exported across the bacterial membrane by a specialized adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporter called PmtCD. In our publication, we have presented the first atomic characterization using a combination of cryoelectron microscopy and x-ray crystallography. We captured the transporter in both ATP-bound and free states, providing mechanistic insight into PSM export. New therapeutics targeting essential virulence determinants such as PmtCD hold promise for alternative treatments and our structures set a foundation for future therapeutic design.
What are the next steps for this research?
Ongoing work is aimed at capturing a structure of PmtCD in complex with a PSM cargo. Although our current structures allow us to speculate as to how PmtCD transports PSMs out of the bacterial cell, capturing a snapshot of this in action will be crucial for both a more in depth understanding of the export mechanism and subsequent structure-guided drug design.