TY - JOUR
T1 - Unexpected link between an antibiotic, pannexin channels and apoptosis
AU - Poon, Ivan K.H.
AU - Chiu, Yu Hsin
AU - Armstrong, Allison J.
AU - Kinchen, Jason M.
AU - Juncadella, Ignacio J.
AU - Bayliss, Douglas A.
AU - Ravichandran, Kodi S.
N1 - Funding Information:
Acknowledgements We thank B. Isakson, M. Billaud, J. Lannigan and other colleagues for discussions. Grants from the US National Institutes of Health (NIGMS 107848 to K.S.R. and D.B.) and the National Health & Medical Research Council of Australia (I.K.H.P.), a training fellowship to I.K.H.P., and the American Heart Association (J.M.K.) supported this work.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897897084&partnerID=8YFLogxK
U2 - 10.1038/nature13147
DO - 10.1038/nature13147
M3 - Article
C2 - 24646995
AN - SCOPUS:84897897084
SN - 0028-0836
VL - 507
SP - 329
EP - 334
JO - Nature
JF - Nature
IS - 7492
ER -