Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing.
Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing.
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DOI：
10.1038/nchembio.153
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发表时间：
2009-04
影响因子：
14.8
通讯作者：
Schramm, Vern L.
中科院分区：
文献类型：
--
作者：
Gutierrez, Jemy A.;Crowder, Tamara;Rinaldo-Matthis, Agnes;Ho, Meng-Chiao;Almo, Steven C.;Schramm, Vern L.
5′-甲基硫代腺苷核苷酶（MTAN）是一种细菌酶，参与S-腺苷甲硫氨酸相关的群体感应途径，诱导细菌致病因子。过渡态类似物5′-甲硫基-（MT-）、5′-乙硫基-（EtT-）和5′-丁硫基-（BuT-）DADMe-ImmucillinAs是霍乱弧菌MTAN（VcMTAN）的缓效、紧密结合抑制剂，解离常数分别为73、70和208 pM。VcMTAN与BuT-DADMe-ImmucillinA的结构分析揭示了有助于高亲和力的相互作用。在霍乱弧菌细胞中，这些化合物是有效的MTAN抑制剂，对MT-、EtT-和BuT-DADMe-ImmucillinA的IC 50值分别为27、31和6 nM，以剂量依赖性方式破坏自身诱导物的产生，而不影响生长。MT-和BuT-DADMe-ImmucillinA也抑制肠出血性大肠杆菌O 157：H7中自诱导物-2的产生，IC 50值分别为600和125 nM。BuT-DADMe-ImmucillinA对两种菌株中自诱导物-2产生的抑制持续几代，并导致生物膜形成减少。这些结果支持了MTAN在群体感应中的作用，以及其作为细菌抗感染药物设计靶点的潜力。
5′-Methylthioadenosine nucleosidase (MTAN) is a bacterial enzyme involved in S-adenosylmethionine-related quorum sensing pathways that induce bacterial pathogenesis factors. Transition state analogues 5′-methylthio- (MT-), 5′-ethylthio- (EtT-) and 5′-butylthio- (BuT-) DADMe-ImmucillinAs are slow-onset, tight-binding inhibitors of Vibrio cholerae MTAN (VcMTAN), with dissociation constants of 73, 70, and 208 pM, respectively. Structural analysis of VcMTAN with BuT-DADMe-ImmucillinA reveals interactions contributing to the high affinity. 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-ImmucillinA, disrupting autoinducer production in a dose-dependent manner without affecting growth. MT- and BuT-DADMe-ImmucillinA also inhibit autoinducer-2 production in enterohemorrhagic Escherichia coli O157:H7 with IC50 values of 600, and 125 nM, respectively. BuT-DADMe-ImmucillinA inhibition of autoinducer-2 production in both strains persists for several generations, and causes reduction in biofilm formation. These results support MTAN’s role in quorum sensing, and its potential as target for bacterial anti-infective drug design.
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影响因子：
3.2
作者：
Balestrino, D;Haagensen, JAJ;Forestier, C
通讯作者：
Forestier, C
影响因子：
7.3
作者：
Evans, GB;Furneaux, RH;Tyler, PC
通讯作者：
Tyler, PC
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.2
作者：
Barrios, AFG;Zuo, RJ;Wood, TK
通讯作者：
Wood, TK
影响因子：
3.6
作者：
Hammer, BK;Bassler, BL
通讯作者：
Bassler, BL