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Unexpected link between an antibiotic, pannexin channels, and apoptosis

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. Although quinolones are widely used to treat bacterial infections, s...

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Autores principales: Poon, Ivan K. H., Chiu, Yu-Hsin, Armstrong, Allison J., Kinchen, Jason M., Juncadella, Ignacio J., Bayliss, Douglas A., Ravichandran, Kodi S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/
https://www.ncbi.nlm.nih.gov/pubmed/24646995
http://dx.doi.org/10.1038/nature13147
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author Poon, Ivan K. H.
Chiu, Yu-Hsin
Armstrong, Allison J.
Kinchen, Jason M.
Juncadella, Ignacio J.
Bayliss, Douglas A.
Ravichandran, Kodi S.
author_facet Poon, Ivan K. H.
Chiu, Yu-Hsin
Armstrong, Allison J.
Kinchen, Jason M.
Juncadella, Ignacio J.
Bayliss, Douglas A.
Ravichandran, Kodi S.
author_sort Poon, Ivan K. H.
collection PubMed
description Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. 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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spelling pubmed-40789912014-09-20 Unexpected link between an antibiotic, pannexin channels, and apoptosis Poon, Ivan K. H. Chiu, Yu-Hsin Armstrong, Allison J. Kinchen, Jason M. Juncadella, Ignacio J. Bayliss, Douglas A. Ravichandran, Kodi S. Nature Article Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. 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. 2014-03-12 2014-03-20 /pmc/articles/PMC4078991/ /pubmed/24646995 http://dx.doi.org/10.1038/nature13147 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Poon, Ivan K. H.
Chiu, Yu-Hsin
Armstrong, Allison J.
Kinchen, Jason M.
Juncadella, Ignacio J.
Bayliss, Douglas A.
Ravichandran, Kodi S.
Unexpected link between an antibiotic, pannexin channels, and apoptosis
title Unexpected link between an antibiotic, pannexin channels, and apoptosis
title_full Unexpected link between an antibiotic, pannexin channels, and apoptosis
title_fullStr Unexpected link between an antibiotic, pannexin channels, and apoptosis
title_full_unstemmed Unexpected link between an antibiotic, pannexin channels, and apoptosis
title_short Unexpected link between an antibiotic, pannexin channels, and apoptosis
title_sort unexpected link between an antibiotic, pannexin channels, and apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/
https://www.ncbi.nlm.nih.gov/pubmed/24646995
http://dx.doi.org/10.1038/nature13147
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