title: Unexpected link between an antibiotic, pannexin channels and apoptosis.
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.
authors.affiliation: 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.
authors.forename: Ivan K H
authors.initials: IK
authors.lastname: Poon
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: 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.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: 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.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.affiliation: 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.
authors.forename: Ignacio J
authors.initials: IJ
authors.lastname: Juncadella
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
authors.affiliation: 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.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D017630:Connexins; D024841:Fluoroquinolones; D009287:Naphthyridines; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; C503631:Panx1 protein, mouse; C080163:trovafloxacin