Unexpected link between an antibiotic, pannexin channels and apoptosis

• Published in: Nature (London) 2014-03, Vol.507 (7492), p.329-334
• Main Authors: Poon, Ivan K. H., Chiu, Yu-Hsin, Armstrong, Allison J., Kinchen, Jason M., Juncadella, Ignacio J., Bayliss, Douglas A., Ravichandran, Kodi S.
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 14/19; 45/29; 45/41; 631/154/1435; 631/80/82/23; 64/110; 9/10; 96/34; 96/95; Animals; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics; Apoptosis; Apoptosis - drug effects; Bacterial diseases; Cell membranes; Cell research; Complications and side effects; Connexins - antagonists & inhibitors; Connexins - deficiency; Connexins - genetics; Connexins - metabolism; Drug Discovery - methods; Female; Flow cytometry; Fluoroquinolones - adverse effects; Fluoroquinolones - blood; Fluoroquinolones - pharmacology; Genetic aspects; Humanities and Social Sciences; Humans; Jurkat Cells; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Naphthyridines - adverse effects; Naphthyridines - blood; Naphthyridines - pharmacology; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phagocytes; Pharmaceutical research; Physiological aspects; Properties; Risk factors; Rodents; Science; Side effects; Stem cells; Testing; Thymocytes - cytology; Thymocytes - drug effects; Thymocytes - metabolism; Trovafloxacin
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13147

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. The pannexin 1 channel on the plasma membrane of apoptotic cells mediates the release of find-me molecular signals to attract phagocytic cells for clearance of the apoptotic cells; here the quinolone antibiotic trovafloxacin is identified as a direct inhibitor of pannexin 1, which results in dysregulated fragmentation of apoptotic cells and may partly explain quinolone toxicity. Dead-cell disposal mechanism clarified The pannexin 1 channel on the plasma membrane of apoptotic cells mediates the release of find-me molecular signals that attract phagocytic cells tasked to clear away the dead cells. In an unbiased screen of small molecules, Kodi Ravichandran and colleagues identify the quinolone antibiotic trovafloxacin as a direct inhibitor of the pannexin 1 channel activity, which results in dysregulated fragmentation of apoptotic cells. This work establishes an essential role for pannexin channels in orderly disassembly of apoptotic cells, and could also re-invigorate interest in quinolone antibiotics without cross-reactivity with the pannexin 1 channel, which may explain the particular toxicity that emerged during clinical trials of trovafloxacin.