Article abstract
Nature Chemical Biology 5, 251 - 257 (2009)
Published online: 8 March 2009 | doi:10.1038/nchembio.153
Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing
Jemy A Gutierrez1, Tamara Crowder1, Agnes Rinaldo-Matthis1, Meng-Chiao Ho1, Steven C Almo1 & Vern L Schramm1
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 IC50 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 IC50 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.
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
Correspondence to: Vern L Schramm1 e-mail: vern@aecom.yu.edu
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