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5'-甲硫基腺苷核苷酶的过渡态类似物破坏群体感应。

Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing.

作者信息

Gutierrez Jemy A, Crowder Tamara, Rinaldo-Matthis Agnes, Ho Meng-Chiao, Almo Steven C, Schramm Vern L

机构信息

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.

出版信息

Nat Chem Biol. 2009 Apr;5(4):251-7. doi: 10.1038/nchembio.153. Epub 2009 Mar 8.

DOI:10.1038/nchembio.153
PMID:19270684
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2743263/
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.

摘要

5'-甲硫基腺苷/S-腺苷高半胱氨酸核苷酶（MTAN）是一种细菌酶，参与诱导细菌致病因子的与S-腺苷甲硫氨酸相关的群体感应途径。过渡态类似物MT-DADMe-免疫青霉素-A、EtT-DADMe-免疫青霉素-A和BuT-DADMe-免疫青霉素-A是霍乱弧菌MTAN（VcMTAN）的慢效、紧密结合抑制剂，其平衡解离常数分别为73、70和208 pM。对VcMTAN与BuT-DADMe-免疫青霉素-A的结构分析揭示了有助于高亲和力的相互作用。我们发现，在霍乱弧菌细胞中，这些化合物是强效的MTAN抑制剂，MT-DADMe-免疫青霉素-A、EtT-DADMe-免疫青霉素-A和BuT-DADMe-免疫青霉素-A的IC50值分别为27、31和6 nM；这些化合物以剂量依赖的方式破坏自诱导物的产生，而不影响生长。MT-DADMe-免疫青霉素-A和BuT-DADMe-免疫青霉素-A还抑制肠出血性大肠杆菌O157:H7中自诱导物-2的产生，IC50值分别为600和125 nM。BuT-DADMe-免疫青霉素-A对两种菌株中自诱导物-2产生的抑制作用持续几代，并导致生物膜形成减少。这些结果支持MTAN在群体感应中的作用及其作为细菌抗感染药物设计靶点的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/702a0e0379f5/nihms93166f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/80f8725142e4/nihms93166f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/db0dc55ecb6e/nihms93166f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/8de8ba91685d/nihms93166f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/702a0e0379f5/nihms93166f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/80f8725142e4/nihms93166f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/db0dc55ecb6e/nihms93166f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/8de8ba91685d/nihms93166f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cb/2743263/702a0e0379f5/nihms93166f4.jpg

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