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Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium

Author

Listed:
  • Andrew M. Hogan

    (University of Manitoba)

  • A. S. M. Zisanur Rahman

    (University of Manitoba)

  • Anna Motnenko

    (University of Manitoba)

  • Aakash Natarajan

    (University of Manitoba)

  • Dustin T. Maydaniuk

    (University of Manitoba)

  • Beltina León

    (Universidad Nacional de La Plata)

  • Zayra Batun

    (University of Manitoba)

  • Armando Palacios

    (University of Manitoba)

  • Alejandra Bosch

    (Universidad Nacional de La Plata)

  • Silvia T. Cardona

    (University of Manitoba
    University of Manitoba)

Abstract

The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.

Suggested Citation

  • Andrew M. Hogan & A. S. M. Zisanur Rahman & Anna Motnenko & Aakash Natarajan & Dustin T. Maydaniuk & Beltina León & Zayra Batun & Armando Palacios & Alejandra Bosch & Silvia T. Cardona, 2023. "Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40494-5
    DOI: 10.1038/s41467-023-40494-5
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    References listed on IDEAS

    as
    1. Edward Geisinger & Nadav J. Mortman & Yunfei Dai & Murat Cokol & Sapna Syal & Andrew Farinha & Delaney G. Fisher & Amy Y. Tang & David W. Lazinski & Stephen Wood & Jon Anthony & Tim Opijnen & Ralph R., 2020. "Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Edward Geisinger & Nadav J. Mortman & Yunfei Dai & Murat Cokol & Sapna Syal & Andrew Farinha & Delaney G. Fisher & Amy Y. Tang & David W. Lazinski & Stephen Wood & Jon Anthony & Tim Opijnen & Ralph R., 2020. "Author Correction: Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    3. Henri Voedts & Sean P. Kennedy & Guennadi Sezonov & Michel Arthur & Jean-Emmanuel Hugonnet, 2022. "Genome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of β-lactams," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Ian J. Roney & David Z. Rudner, 2023. "Two broadly conserved families of polyprenyl-phosphate transporters," Nature, Nature, vol. 613(7945), pages 729-734, January.
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