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
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Biofilms / drug effects
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Biofilms / growth & development
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Enterohemorrhagic Escherichia coli / drug effects
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Enterohemorrhagic Escherichia coli / enzymology*
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Enterohemorrhagic Escherichia coli / genetics
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Enterohemorrhagic Escherichia coli / metabolism
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Escherichia coli Proteins / antagonists & inhibitors*
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Escherichia coli Proteins / chemistry
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Escherichia coli Proteins / metabolism
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Gene Expression Regulation, Bacterial
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Models, Molecular
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Molecular Structure
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N-Glycosyl Hydrolases / antagonists & inhibitors*
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N-Glycosyl Hydrolases / chemistry
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N-Glycosyl Hydrolases / metabolism
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Pyrrolidines / pharmacology
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Quorum Sensing / drug effects*
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Substrate Specificity
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Vibrio cholerae / drug effects
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Vibrio cholerae / enzymology*
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Vibrio cholerae / genetics
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Vibrio cholerae / metabolism
Substances
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Escherichia coli Proteins
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Pyrrolidines
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N-Glycosyl Hydrolases
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5'-methylthioadenosine nucleosidase, E coli
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Adenine
Associated data
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PDB/1Z5P
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PDB/3DP9
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PubChem-Substance/57244598
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PubChem-Substance/57244599
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PubChem-Substance/57244600
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PubChem-Substance/57244601
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PubChem-Substance/57244602
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PubChem-Substance/57244603
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PubChem-Substance/57244604
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PubChem-Substance/57244605
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PubChem-Substance/57244606
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PubChem-Substance/57244607
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PubChem-Substance/57244608
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PubChem-Substance/57244609
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PubChem-Substance/57244610
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PubChem-Substance/57244611
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PubChem-Substance/57244612
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PubChem-Substance/57244613
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PubChem-Substance/57244614
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PubChem-Substance/57244615