title: Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing.
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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jemy A
authors.initials: JA
authors.lastname: Gutierrez
authors.forename: Tamara
authors.initials: T
authors.lastname: Crowder
authors.forename: Agnes
authors.initials: A
authors.lastname: Rinaldo-Matthis
authors.forename: Meng-Chiao
authors.initials: MC
authors.lastname: Ho
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D054324:Enterohemorrhagic Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D015394:Molecular Structure; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D053038:Quorum Sensing / Q000187:drug effects*; D013379:Substrate Specificity; D014734:Vibrio cholerae / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D011759:Pyrrolidines; D009699:N-Glycosyl Hydrolases; C505576:5'-methylthioadenosine nucleosidase, E coli; D000225:Adenine