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A new antibiotic traps lipopolysaccharide in its intermembrane transporter

Author

Listed:
  • Karanbir S. Pahil

    (Harvard University)

  • Morgan S. A. Gilman

    (Harvard Medical School)

  • Vadim Baidin

    (Harvard University)

  • Thomas Clairfeuille

    (Roche Innovation Center Basel)

  • Patrizio Mattei

    (Roche Innovation Center Basel)

  • Christoph Bieniossek

    (Roche Innovation Center Basel)

  • Fabian Dey

    (Roche Innovation Center Basel)

  • Dieter Muri

    (Roche Innovation Center Basel)

  • Remo Baettig

    (Roche Innovation Center Basel)

  • Michael Lobritz

    (Roche Innovation Center Basel)

  • Kenneth Bradley

    (Roche Innovation Center Basel)

  • Andrew C. Kruse

    (Harvard Medical School)

  • Daniel Kahne

    (Harvard University)

Abstract

Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet1. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics2–6. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought7–9. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.

Suggested Citation

  • Karanbir S. Pahil & Morgan S. A. Gilman & Vadim Baidin & Thomas Clairfeuille & Patrizio Mattei & Christoph Bieniossek & Fabian Dey & Dieter Muri & Remo Baettig & Michael Lobritz & Kenneth Bradley & An, 2024. "A new antibiotic traps lipopolysaccharide in its intermembrane transporter," Nature, Nature, vol. 625(7995), pages 572-577, January.
  • Handle: RePEc:nat:nature:v:625:y:2024:i:7995:d:10.1038_s41586-023-06799-7
    DOI: 10.1038/s41586-023-06799-7
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    Cited by:

    1. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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