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

Nathanael A. Caveney, Guillermo Caballero, Henri Voedts, Ana Niciforovic, Liam J. Worrall, Marija Vuckovic, Matthieu Fonvielle, Jean-Emmanuel Hugonnet, Michel Arthur and Natalie C. J. Strynadka ()
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Nathanael A. Caveney: University of British Columbia
Guillermo Caballero: University of British Columbia
Henri Voedts: Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC
Ana Niciforovic: University of British Columbia
Liam J. Worrall: University of British Columbia
Marija Vuckovic: University of British Columbia
Matthieu Fonvielle: Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC
Jean-Emmanuel Hugonnet: Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC
Michel Arthur: Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, INSERM, Centre de Recherche des Cordeliers, CRC
Natalie C. J. Strynadka: University of British Columbia

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09507-0

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