（《自然—化学生物学》（Nature Chemical Biology），doi:10.1038/nchembio.153，Jemy A Gutierrez，Vern L Schramm）
Nature Chemical Biology
Published online: 8 March 2009 | doi :10.1038/nchembio.153
Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing
Jemy A Gutierrez 1 , Tamara Crowder 1 , Agnes Rinaldo-Matthis 1 , Meng-Chiao Ho 1 , Steven C Almo 1 & Vern L Schramm 1
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 ( Vc MTAN), with equilibrium dissociation constants of 73, 70 and 208 pM, respectively. Structural analysis of Vc MTAN 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.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.