Unexpected link between an antibiotic, pannexin channels and apoptosis

  • Nature. 2014 Mar 20;507(7492):329-34. doi: 10.1038/nature13147.
Ivan K H Poon  1 ,  Yu-Hsin Chiu  2 ,  Allison J Armstrong  3 ,  Jason M Kinchen  3 ,  Ignacio J Juncadella  3 ,  Douglas A Bayliss  2 ,  Kodi S Ravichandran  3
Affiliations
  • 1. 1] The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA [3] Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA [4] La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
  • 2. Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
  • 3. 1] The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA [3] Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
PMID: 24646995 DOI: 10.1038/nature13147
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.

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