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Unexpected link between an antibiotic, pannexin channels and apoptosis

Author

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  • Ivan K. H. Poon

    (The Center for Cell Clearance, University of Virginia
    Immunology, and Cancer Biology, University of Virginia
    Beirne B. Carter Center for Immunology Research, University of Virginia
    La Trobe Institute for Molecular Science, La Trobe University)

  • Yu-Hsin Chiu

    (University of Virginia)

  • Allison J. Armstrong

    (The Center for Cell Clearance, University of Virginia
    Immunology, and Cancer Biology, University of Virginia
    Beirne B. Carter Center for Immunology Research, University of Virginia)

  • Jason M. Kinchen

    (The Center for Cell Clearance, University of Virginia
    Immunology, and Cancer Biology, University of Virginia
    Beirne B. Carter Center for Immunology Research, University of Virginia)

  • Ignacio J. Juncadella

    (The Center for Cell Clearance, University of Virginia
    Immunology, and Cancer Biology, University of Virginia
    Beirne B. Carter Center for Immunology Research, University of Virginia)

  • Douglas A. Bayliss

    (University of Virginia)

  • Kodi S. Ravichandran

    (The Center for Cell Clearance, University of Virginia
    Immunology, and Cancer Biology, University of Virginia
    Beirne B. Carter Center for Immunology Research, University of Virginia)

Abstract

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. Here we show that the quinolone antibiotic trovafloxacin is a novel PANX1 inhibitor, by using a small-molecule screen. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children. PANX1 is a direct target of trovafloxacin at drug concentrations seen in human plasma, and its inhibition led to dysregulated fragmentation of apoptotic cells. Genetic loss of PANX1 phenocopied trovafloxacin effects, revealing a non-redundant role for pannexin channels in regulating cellular disassembly during apoptosis. Increase in drug-resistant bacteria worldwide and the dearth of new antibiotics is a major human health challenge. Comparing different quinolone antibiotics suggests that certain structural features may contribute to PANX1 blockade. These data identify a novel linkage between an antibiotic, pannexin channels and cellular integrity, and suggest that re-engineering certain quinolones might help develop newer antibacterials.

Suggested Citation

  • Ivan K. H. Poon & Yu-Hsin Chiu & Allison J. Armstrong & Jason M. Kinchen & Ignacio J. Juncadella & Douglas A. Bayliss & Kodi S. Ravichandran, 2014. "Unexpected link between an antibiotic, pannexin channels and apoptosis," Nature, Nature, vol. 507(7492), pages 329-334, March.
    • Handle: RePEc:nat:nature:v:507:y:2014:i:7492:d:10.1038_nature13147
    DOI: 10.1038/nature13147
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