This week we profile a recent publication in Nature Communications from Nathanael Caveney
(pictured) in the laboratory of Dr. Natalie Strynadka at the Centre for Blood Research and 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?
In Escherichia coli, the peptidoglycan crosslinking reaction to form the cell wall is primarily carried out by penicillin-binding proteins that catalyse D,D-transpeptidase activity. However, an alternate crosslinking mechanism involving the L,D-transpeptidase YcbB can lead to bypass of D,D-transpeptidation and beta-lactam resistance. YcbB has also recently been implicated in rescue of outer membrane stress, bacterial susceptibility to copper, and release of Typhi toxin from Salmonella. Due to the important roles YcbB can undertake during stress and infectious conditions, it is a promising target for the development of novel and specific antibacterial therapies. Our crystal structure of YcbB in complex with meropenem gives insight into the mode of inhibition by carbapenems, the singular antibiotic class with significant activity against L,D-transpeptidases. Additionally, we probed the interaction network of this pathway and assayed beta-lactam resistance in vivo. Our results provide the first structural insights into the mechanism of action and the inhibition of L,D-transpeptidation in Gram negative bacteria, and into YcbB-mediated antibiotic resistance.
What are the next steps for this research?
We hope to use this structural knowledge to study the role of YcbB in bacterial infection. Downstream we hope to develop novel inhibitors of YcbB that allow for targeting of L,D-transpeptidation while permitting D,D-transpeptidation of the bacteria during noninvasive conditions.
This research was funded by:
This work was funded by operating grants to NCJS from JPIAMR-CIHR (Joint Program Initiative in Antimicrobial Resistance involving investigators from France, the Netherlands and the UK) and the Howard Hughes International Senior Scholar program. We also acknowledge infrastructure funding from the Canadian Foundation of Innovation and British Columbia Knowledge Development Fund. NAC holds an NSERC Postgraduate Scholarship-Doctoral and a Centre for Blood Research Graduate Award and NCJS is a Tier I Canada Research Chair in Antibiotic Discovery. Research described in this paper was in part performed using beamline 08ID-1 at the Canadian Light Source and beamline 501 at the Advanced Light Source. The Canadian Light Source is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, Western Economic Diversification Canada, the National Research Council Canada, and the Canadian Institutes of Health Research. The Advanced Light Source is a DOE Office of Science User Facility.
