Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09507-0
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Funding
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- University of Saskatchewan
- Government of Saskatchewan
- Western Economic Diversification Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- JPIAMR-CIHR
- Howard Hughes International Senior Scholar program
- project NAPCLI from the JPI AMR program [ANR-14-JAMR-0003-01]
- Canadian Foundation of Innovation
- British Columbia Knowledge Development Fund
- Agence Nationale de la Recherche (ANR) [ANR-14-JAMR-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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The bacterial cell wall plays a crucial role in viability and is an important drug target. 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. Here, we show that the crystallographic structure of YcbB consists of a conserved L,D-transpeptidase catalytic domain decorated with a subdomain on the dynamic substrate capping loop, peptidoglycan-binding and large scaffolding domains. Meropenem acylation of YcbB gives insight into the mode of inhibition by carbapenems, the singular antibiotic class with significant activity against L,D-transpeptidases. We also report the structure of PBP5-meropenem to compare interactions mediating inhibition. Additionally, we probe the interaction network of this pathway and assay beta-lactam resistance in vivo. Our results provide structural insights into the mechanism of action and the inhibition of L,D-transpeptidation, and into YcbB-mediated antibiotic resistance.
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