TY - JOUR
T1 - ppGpp analogues inhibit synthetase activity of Rel proteins from Gram-negative and Gram-positive bacteria
AU - Wexselblatt, Ezequiel
AU - Katzhendler, Jehoshua
AU - Saleem-Batcha, Raspudin
AU - Hansen, Guido
AU - Hilgenfeld, Rolf
AU - Glaser, Gad
AU - Vidavski, Roee R.
PY - 2010/6/15
Y1 - 2010/6/15
N2 - A prominent feature of the stringent response is the accumulation of two unusual phosphorylated derivatives of GTP and GDP (pppGpp: 5′-triphosphate-3′-diphosphate, and ppGpp: 5′-3′-bis-diphosphate), collectively called (p)ppGpp, within a few seconds after the onset of amino-acid starvation. The synthesis of these 'alarmone' compounds is catalyzed by RelA homologues. Other features of the stringent response include inhibition of stable RNA synthesis and modulation of transcription, replication, and translation. (p)ppGpp accumulation is important for virulence induction, differentiation and antibiotic resistance. We have synthesized a group of (p)ppGpp analogues and tested them as competitive inhibitors of Rel proteins in vitro. 2′-Deoxyguanosine-3′-5′-di(methylene bisphosphonate) [compound (10)] was found as an inhibitor that reduces ppGpp formation in both Gram-negative and Gram-positive bacteria. In silico docking together with competitive inhibition analysis suggests that compound (10) inhibits activity of Rel proteins by competing with GTP/GDP for its binding site. As Rel proteins are completely absent in mammalians, this appears to be a very attractive approach for the development of novel antibacterial agents.
AB - A prominent feature of the stringent response is the accumulation of two unusual phosphorylated derivatives of GTP and GDP (pppGpp: 5′-triphosphate-3′-diphosphate, and ppGpp: 5′-3′-bis-diphosphate), collectively called (p)ppGpp, within a few seconds after the onset of amino-acid starvation. The synthesis of these 'alarmone' compounds is catalyzed by RelA homologues. Other features of the stringent response include inhibition of stable RNA synthesis and modulation of transcription, replication, and translation. (p)ppGpp accumulation is important for virulence induction, differentiation and antibiotic resistance. We have synthesized a group of (p)ppGpp analogues and tested them as competitive inhibitors of Rel proteins in vitro. 2′-Deoxyguanosine-3′-5′-di(methylene bisphosphonate) [compound (10)] was found as an inhibitor that reduces ppGpp formation in both Gram-negative and Gram-positive bacteria. In silico docking together with competitive inhibition analysis suggests that compound (10) inhibits activity of Rel proteins by competing with GTP/GDP for its binding site. As Rel proteins are completely absent in mammalians, this appears to be a very attractive approach for the development of novel antibacterial agents.
KW - Antibacterial
KW - ppGpp
KW - RelA
KW - Stringent response
UR - http://www.scopus.com/inward/record.url?scp=77953134680&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2010.04.064
DO - 10.1016/j.bmc.2010.04.064
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C2 - 20483622
AN - SCOPUS:77953134680
SN - 0968-0896
VL - 18
SP - 4485
EP - 4497
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 12
ER -