Thiamine pyrophosphate riboswitches are targets for the antimicrobial compound pyrithiamine
Thiamine pyrophosphate riboswitches are targets for the antimicrobial compound pyrithiamine
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DOI：
10.1016/j.chembiol.2005.10.007
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发表时间：
2005-12-01
影响因子：
--
通讯作者：
Breaker, RR
中科院分区：
文献类型：
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作者：
Sudarsan, N;Cohen-Chalamish, S;Breaker, RR
硫胺素代谢基因在许多细菌中由一个核糖开关类结合辅酶硫胺素焦磷酸(TPP)调节。我们证明硫胺素类似物吡硫胺(PT)的抗菌作用是通过与细菌和真菌中的TPP核糖开关相互作用来实现的。例如，焦磷酸吡硫胺(PTPP)与控制枯草杆菌中Tena操纵子的TPP核糖开关结合。当在硫胺或PT存在下生长时，TPP核糖开关调控的报告基因在转基因枯草杆菌或大肠杆菌中的表达减少，而这些生物中的突变核糖开关对这些配体没有反应。选择耐PT的细菌携带特定的突变，破坏与TPP核糖开关的配体结合，并解除对某些TPP代谢基因的抑制。我们的发现表明，核糖开关可以作为抗菌药物的靶点，并扩大了我们对细菌中硫胺素代谢的理解。
Thiamine metabolism genes are regulated in numerous bacteria by a riboswitch class that binds the coenzyme thiamine pyrophosphate (TPP). We demonstrate that the antimicrobial action of the thiamine analog pyrithiamine (PT) is mediated by interaction with TPP riboswitches in bacteria and fungi. For example, pyrithiamine pyrophosphate (PTPP) binds the TPP riboswitch controlling the tenA operon in Bacillus subtilis. Expression of a TPP riboswitch-regulated reporter gene is reduced in transgenic B. subtilis or Escherichia coli when grown in the presence of thiamine or PT, while mutant riboswitches in these organisms are unresponsive to these ligands. Bacteria selected for PT resistance bear specific mutations that disrupt ligand binding to TPP riboswitches and derepress certain TPP metabolic genes. Our findings demonstrate that riboswitches can serve as antimicrobial drug targets and expand our understanding of thiamine metabolism in bacteria.