Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing

Nat Chem Biol. 2009 Apr;5(4):251-7. doi: 10.1038/nchembio.153. Epub 2009 Mar 8.

Abstract

5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a bacterial enzyme involved in S-adenosylmethionine-related quorum sensing pathways that induce bacterial pathogenesis factors. Transition state analogs MT-DADMe-Immucillin-A, EtT-DADMe-Immucillin-A and BuT-DADMe-Immucillin-A are slow-onset, tight-binding inhibitors of Vibrio cholerae MTAN (VcMTAN), with equilibrium dissociation constants of 73, 70 and 208 pM, respectively. Structural analysis of VcMTAN with BuT-DADMe-Immucillin-A revealed interactions contributing to the high affinity. We found that in V. cholerae cells, these compounds are potent MTAN inhibitors with IC(50) values of 27, 31 and 6 nM for MT-, EtT- and BuT-DADMe-Immucillin-A, respectively; the compounds disrupt autoinducer production in a dose-dependent manner without affecting growth. MT- and BuT-DADMe-Immucillin-A also inhibited autoinducer-2 production in enterohemorrhagic Escherichia coli O157:H7 with IC(50) values of 600 and 125 nM, respectively. BuT-DADMe-Immucillin-A inhibition of autoinducer-2 production in both strains persisted for several generations and caused reduction in biofilm formation. These results support MTAN's role in quorum sensing and its potential as a target for bacterial anti-infective drug design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Enterohemorrhagic Escherichia coli / drug effects
  • Enterohemorrhagic Escherichia coli / enzymology*
  • Enterohemorrhagic Escherichia coli / genetics
  • Enterohemorrhagic Escherichia coli / metabolism
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Gene Expression Regulation, Bacterial
  • Models, Molecular
  • Molecular Structure
  • N-Glycosyl Hydrolases / antagonists & inhibitors*
  • N-Glycosyl Hydrolases / chemistry
  • N-Glycosyl Hydrolases / metabolism
  • Pyrrolidines / pharmacology
  • Quorum Sensing / drug effects*
  • Substrate Specificity
  • Vibrio cholerae / drug effects
  • Vibrio cholerae / enzymology*
  • Vibrio cholerae / genetics
  • Vibrio cholerae / metabolism

Substances

  • Escherichia coli Proteins
  • Pyrrolidines
  • N-Glycosyl Hydrolases
  • 5'-methylthioadenosine nucleosidase, E coli
  • Adenine

Associated data

  • PDB/1Z5P
  • PDB/3DP9
  • PubChem-Substance/57244598
  • PubChem-Substance/57244599
  • PubChem-Substance/57244600
  • PubChem-Substance/57244601
  • PubChem-Substance/57244602
  • PubChem-Substance/57244603
  • PubChem-Substance/57244604
  • PubChem-Substance/57244605
  • PubChem-Substance/57244606
  • PubChem-Substance/57244607
  • PubChem-Substance/57244608
  • PubChem-Substance/57244609
  • PubChem-Substance/57244610
  • PubChem-Substance/57244611
  • PubChem-Substance/57244612
  • PubChem-Substance/57244613
  • PubChem-Substance/57244614
  • PubChem-Substance/57244615