4.8 Article

Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli

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NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09507-0

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资金

  1. Canada Foundation for Innovation
  2. Natural Sciences and Engineering Research Council of Canada
  3. University of Saskatchewan
  4. Government of Saskatchewan
  5. Western Economic Diversification Canada
  6. National Research Council Canada
  7. Canadian Institutes of Health Research
  8. DOE Office of Science User Facility [DE-AC02-05CH11231]
  9. JPIAMR-CIHR
  10. Howard Hughes International Senior Scholar program
  11. project NAPCLI from the JPI AMR program [ANR-14-JAMR-0003-01]
  12. Canadian Foundation of Innovation
  13. British Columbia Knowledge Development Fund
  14. 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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