Cryo-EM characterization of the anydromuropeptide permease AmpG central to bacterial fitness and β-lactam antibiotic resistance

Helena E. Sverak, Luke N. Yaeger, Liam J. Worrall, Condurache M. Vacariu, Amy J. Glenwright, Marija Vuckovic, Zayni-Dean Al Azawi, Ryan P. Lamers, Victoria A. Marko, Clarissa Skorupski, Arvind S. Soni, Martin E. Tanner, Lori L. Burrows and Natalie CJ Strynadka ()
Additional contact information
Helena E. Sverak: University of British Columbia
Luke N. Yaeger: Hamilton
Liam J. Worrall: University of British Columbia
Condurache M. Vacariu: University of British Columbia
Amy J. Glenwright: University of British Columbia
Marija Vuckovic: University of British Columbia
Zayni-Dean Al Azawi: Hamilton
Ryan P. Lamers: Hamilton
Victoria A. Marko: Hamilton
Clarissa Skorupski: Hamilton
Arvind S. Soni: University of British Columbia
Martin E. Tanner: University of British Columbia
Lori L. Burrows: Hamilton
Natalie CJ Strynadka: University of British Columbia

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Bacteria invest significant resources into the continuous creation and tailoring of their essential protective peptidoglycan (PG) cell wall. Several soluble PG biosynthesis products in the periplasm are transported to the cytosol for recycling, leading to enhanced bacterial fitness. GlcNAc-1,6-anhydroMurNAc and peptide variants are transported by the essential major facilitator superfamily importer AmpG in Gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Accumulation of GlcNAc-1,6-anhydroMurNAc-pentapeptides also results from β-lactam antibiotic induced cell wall damage. In some species, these products upregulate the β-lactamase AmpC, which hydrolyzes β-lactams to allow for bacterial survival and drug-resistant infections. Here, we have used cryo-electron microscopy and chemical synthesis of substrates in an integrated structural, biochemical, and cellular analysis of AmpG. We show how AmpG accommodates the large GlcNAc-1,6-anhydroMurNAc peptides, including a unique hydrophobic vestibule to the substrate binding cavity, and characterize residues involved in binding that inform the mechanism of proton-mediated transport.

Date: 2024
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DOI: 10.1038/s41467-024-54219-9

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