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Pahil, Karanbir

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Pahil

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Karanbir

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Pahil, Karanbir

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Author's Publications: search.filters.isAuthorOfPublication.9642a8db-1c72-4e9a-9a13-442028805295

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    A novel antibiotic class targeting the lipopolysaccharide transporter
    (Springer Science and Business Media LLC, 2024-01-03) Zampaloni, Claudia; Mattei, Patrizio; Bleicher, Konrad; Winther, Lotte; Thäte, Claudia; Bucher, Christian; Adam, Jean-Michel; Alanine, Alexander; Amrein, Kurt E.; Baidin, Vadim; Bieniossek, Christoph; Bissantz, Caterina; Boess, Franziska; Cantrill, Carina; Clairfeuille, Thomas; Dey, Fabian; Di Giorgio, Patrick; du Castel, Pauline; Dylus, David; Dzygiel, Pawel; Felici, Antonio; García-Alcalde, Fernando; Haldimann, Andreas; Leipner, Matthew; Leyn, Semen; Louvel, Séverine; Misson, Pauline; Osterman, Andrei; Pahil, Karanbir; Rigo, Sébastien; Schäublin, Adrian; Scharf, Sebastian; Schmitz, Petra; Stoll, Theodor; Trauner, Andrej; Zoffmann, Sannah; Kahne, Daniel; Young, John A. T.; Lobritz, Michael A.; Bradley, Kenneth A.
    Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.
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    Structural Basis of Unidirectional Export of Lipopolysaccharide to the Cell Surface
    (Springer Science and Business Media LLC, 2019-03) Kahne, Daniel; Owens, Tristan; Taylor, Rebecca; Pahil, Karanbir; Bertani, Blake; Ruiz, Natividad; Kruse, Andrew
    Gram-negative bacteria are surrounded by an inner cytoplasmic membrane and by an outer membrane, which serves as a protective barrier to limit entry of many antibiotics. The distinctive properties of the outer membrane are due to the presence of lipopolysaccharide1. This large glycolipid, which contains numerous sugars, is made in the cytoplasm; a complex of proteins forms a membrane-to-membrane bridge that mediates transport of lipopolysaccharide from the inner membrane to the cell surface1. The inner-membrane components of the protein bridge comprise an ATP-binding cassette transporter that powers transport, but how this transporter ensures unidirectional lipopolysaccharide movement across the bridge to the outer membrane is unknown2. Here we describe two crystal structures of a five-component inner-membrane complex that contains all the proteins required to extract lipopolysaccharide from the membrane and pass it to the protein bridge. Analysis of these structures, combined with biochemical and genetic experiments, identifies the path of lipopolysaccharide entry into the cavity of the transporter and up to the bridge. We also identify a protein gate that must open to allow movement of substrate from the cavity onto the bridge. Lipopolysaccharide entry into the cavity is ATP-independent, but ATP is required for lipopolysaccharide movement past the gate and onto the bridge. Our findings explain how the inner-membrane transport complex controls efficient unidirectional transport of lipopolysaccharide against its concentration gradient.