ppGpp analogues inhibit synthetase activity of Rel proteins from Gram-negative and Gram-positive bacteria

Ezequiel Wexselblatt, Jehoshua Katzhendler*, Raspudin Saleem-Batcha, Guido Hansen, Rolf Hilgenfeld, Gad Glaser, Roee R. Vidavski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4485-4497
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number12
DOIs
StatePublished - 15 Jun 2010

Keywords

  • Antibacterial
  • ppGpp
  • RelA
  • Stringent response

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