Publication Date:
2014-03-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poon, Ivan K H -- Chiu, Yu-Hsin -- Armstrong, Allison J -- Kinchen, Jason M -- Juncadella, Ignacio J -- Bayliss, Douglas A -- Ravichandran, Kodi S -- 107848/PHS HHS/ -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 GM107848/GM/NIGMS NIH HHS/ -- T32 AI007496/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Mar 20;507(7492):329-34. doi: 10.1038/nature13147. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24646995" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Bacterial Agents/*adverse effects/blood/*pharmacology
;
Apoptosis/*drug effects
;
Connexins/*antagonists & inhibitors/deficiency/genetics/metabolism
;
Drug Discovery/methods
;
Female
;
Fluoroquinolones/*adverse effects/blood/*pharmacology
;
Humans
;
Jurkat Cells
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Naphthyridines/*adverse effects/blood/*pharmacology
;
Nerve Tissue Proteins/*antagonists & inhibitors/deficiency/genetics/metabolism
;
Thymocytes/cytology/drug effects/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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