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, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

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.

Original languageEnglish
Pages (from-to)329-334
Number of pages6
JournalNature
Volume507
Issue number7492
DOIs
StatePublished - 2014

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