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Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding

Author

Listed:
  • Ladan Khodaparast

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Laleh Khodaparast

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Guiqin Wu

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Emiel Michiels

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Rodrigo Gallardo

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Bert Houben

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Teresa Garcia

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Matthias Vleeschouwer

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Meine Ramakers

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Hannah Wilkinson

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Ramon Duran-Romaña

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Johan Eldere

    (Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology & Immunology, KU Leuven)

  • Frederic Rousseau

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

  • Joost Schymkowitz

    (Switch Laboratory, VIB Center for Brain and Disease Research
    Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven)

Abstract

There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down beta-lactam rings. We have observed that certain beta-lactamases tend to aggregate, which persists throughout their evolution under the selective pressure of antibiotics on their active sites. Interestingly, we find that existing beta-lactamase active site inhibitors can act as molecular chaperones, promoting the proper folding of these resistance factors. Therefore, we have created Pept-Ins, synthetic peptides designed to exploit the structural weaknesses of beta-lactamases by causing them to misfold into intracellular inclusion bodies. This approach restores sensitivity to a wide range of beta-lactam antibiotics in resistant clinical isolates, including those with Extended Spectrum variants that pose significant challenges in medical practice. Our findings suggest that targeted aggregation of resistance factors could offer a strategy for identifying molecules that aid in addressing the global antibiotic resistance crisis.

Suggested Citation

  • Ladan Khodaparast & Laleh Khodaparast & Guiqin Wu & Emiel Michiels & Rodrigo Gallardo & Bert Houben & Teresa Garcia & Matthias Vleeschouwer & Meine Ramakers & Hannah Wilkinson & Ramon Duran-Romaña & J, 2023. "Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41191-z
    DOI: 10.1038/s41467-023-41191-z
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    References listed on IDEAS

    as
    1. Ladan Khodaparast & Laleh Khodaparast & Rodrigo Gallardo & Nikolaos N. Louros & Emiel Michiels & Reshmi Ramakrishnan & Meine Ramakers & Filip Claes & Lydia Young & Mohammad Shahrooei & Hannah Wilkinso, 2018. "Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Karyn Hede, 2014. "Antibiotic resistance: An infectious arms race," Nature, Nature, vol. 509(7498), pages 2-3, May.
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