Unexpected link between an antibiotic, pannexin channels and apoptosis

摘要

凋亡细胞的胞质膜上的Pamexin 1通道介导"find-me"分子信号的释放，这种信号吸引吞噬细胞，后者的任务是清除死亡的细胞。在对小分子所做的一项无偏筛选中，Kodi Ravichandran及同事发现喹诺酮抗体Trova-floxacin是Pannexin 1通道活性的一种直接抑制分子，导致凋亡细胞的失控碎片化。这项工作确定了Pannexin通道在凋亡细胞的有序分解中扮演一个必要角色，同时还可能重新激发人们对与Pannexin 1通道没有交叉反应的喹诺酮抗体的兴趣，这种交叉反应也许可解释在Trova-floxacin的临床试验中所出现的特别毒性。%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.