Unexpected link between an antibiotic, pannexin channels and apoptosis

Ivan K. H. Poon, Yu-Hsin Chiu, Allison J. Armstrong, Jason M. Kinchen, Ignacio J. Juncadella, Douglas A. Bayliss and Kodi S. Ravichandran ()
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Ivan K. H. Poon: The Center for Cell Clearance, University of Virginia
Yu-Hsin Chiu: University of Virginia
Allison J. Armstrong: The Center for Cell Clearance, University of Virginia
Jason M. Kinchen: The Center for Cell Clearance, University of Virginia
Ignacio J. Juncadella: The Center for Cell Clearance, University of Virginia
Douglas A. Bayliss: University of Virginia
Kodi S. Ravichandran: The Center for Cell Clearance, University of Virginia

Nature, 2014, vol. 507, issue 7492, 329-334

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13147

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