Unexpected Link Between an Antibiotic, Pannexin Channels and Apoptosis

Nature. 2014 Mar 20;507(7492):329-34. doi: 10.1038/nature13147. Epub 2014 Mar 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / adverse effects*
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacology*
  • Apoptosis / drug effects*
  • Connexins / antagonists & inhibitors*
  • Connexins / deficiency
  • Connexins / genetics
  • Connexins / metabolism
  • Drug Discovery / methods
  • Female
  • Fluoroquinolones / adverse effects*
  • Fluoroquinolones / blood
  • Fluoroquinolones / pharmacology*
  • Humans
  • Jurkat Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naphthyridines / adverse effects*
  • Naphthyridines / blood
  • Naphthyridines / pharmacology*
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Thymocytes / cytology
  • Thymocytes / drug effects
  • Thymocytes / metabolism

Substances

  • Anti-Bacterial Agents
  • Connexins
  • Fluoroquinolones
  • Naphthyridines
  • Nerve Tissue Proteins
  • PANX1 protein, human
  • Panx1 protein, mouse
  • trovafloxacin