A new antibiotic traps lipopolysaccharide in its intermembrane transporter

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, Andrew C. Kruse () and Daniel Kahne ()
Additional contact information
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

Nature, 2024, vol. 625, issue 7995, 572-577

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06799-7

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