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Unexpected link between an antibiotic, pannexin channels, and apoptosis
Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. Although quinolones are widely used to treat bacterial infections, s...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/ https://www.ncbi.nlm.nih.gov/pubmed/24646995 http://dx.doi.org/10.1038/nature13147 |
Sumario: | Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. 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. |
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