1. Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing
- Author
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Meng-Chiao Ho, Agnes Rinaldo-Matthis, Jemy A. Gutierrez, Tamara Crowder, Steven C. Almo, and Vern L. Schramm
- Subjects
Models, Molecular ,Pyrrolidines ,medicine.disease_cause ,Article ,Substrate Specificity ,Methylthioadenosine nucleosidase ,Transition state analog ,medicine ,Molecular Biology ,Escherichia coli ,N-Glycosyl Hydrolases ,Vibrio cholerae ,chemistry.chemical_classification ,Molecular Structure ,Chemistry ,Adenine ,Escherichia coli Proteins ,Biofilm ,Quorum Sensing ,Cell Biology ,Gene Expression Regulation, Bacterial ,Quorum sensing ,Enzyme ,Biochemistry ,Biofilms ,Enterohemorrhagic Escherichia coli ,Autoinducer - 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.
- Published
- 2008