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Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

Author

Listed:
  • Edward Geisinger

    (Northeastern University
    Tufts University School of Medicine)

  • Nadav J. Mortman

    (Tufts University School of Medicine)

  • Yunfei Dai

    (Northeastern University)

  • Murat Cokol

    (Tufts University School of Medicine
    Harvard Medical School)

  • Sapna Syal

    (Tufts University School of Medicine)

  • Andrew Farinha

    (Northeastern University)

  • Delaney G. Fisher

    (Tufts University School of Medicine)

  • Amy Y. Tang

    (Northeastern University)

  • David W. Lazinski

    (Tufts University School of Medicine)

  • Stephen Wood

    (Boston College)

  • Jon Anthony

    (Boston College)

  • Tim Opijnen

    (Boston College)

  • Ralph R. Isberg

    (Tufts University School of Medicine)

Abstract

A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18301-2
    DOI: 10.1038/s41467-020-18301-2
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    Cited by:

    1. 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.
    2. Dmitry Leshchiner & Federico Rosconi & Bharathi Sundaresh & Emily Rudmann & Luisa Maria Nieto Ramirez & Andrew T. Nishimoto & Stephen J. Wood & Bimal Jana & Noemí Buján & Kaicheng Li & Jianmin Gao & M, 2022. "A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Lucas Serra Moncadas & Cyrill Hofer & Paul-Adrian Bulzu & Jakob Pernthaler & Adrian-Stefan Andrei, 2024. "Freshwater genome-reduced bacteria exhibit pervasive episodes of adaptive stasis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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