Novel riboswitch ligand analogs as selective inhibitors of guanine-related metabolic pathways.
Novel riboswitch ligand analogs as selective inhibitors of guanine-related metabolic pathways.
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DOI：
10.1371/journal.ppat.1000865
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发表时间：
2010-04-22
期刊：
影响因子：
6.7
通讯作者：
Lafontaine DA
中科院分区：
文献类型：
--
作者：
Mulhbacher J;Brouillette E;Allard M;Fortier LC;Malouin F;Lafontaine DA
核糖开关是调节基因表达以响应特定代谢物结合的调节元件。最近有报道称，核糖开关激动剂可能通过与核糖开关结构域结合而显示出抗菌特性。鸟嘌呤核糖开关参与了嘌呤代谢产物的运输和生物合成的调节，这对核苷酸细胞库是至关重要的。在鸟嘌呤结合后，这些核糖开关稳定了5‘-未翻译的mRNA结构，导致下游开放阅读框架的转录衰减。原则上，任何针对鸟嘌呤核糖开关的激动型化合物都可能导致基因抑制，即使在细胞缺乏鸟嘌呤的时候也是如此。与核糖开关结合的抗生素提供了可以根据核糖开关晶体结构进行合理设计的新型抗菌化合物。利用这一点，我们已经鉴定出一种与鸟嘌呤核糖开关结合的嘧啶化合物(PC1)，它对包括众所周知的医院病原体在内的一类细菌具有杀菌活性。只有当编码GMP合成酶的基因guaA处于核糖开关的控制下时，这种选择性杀菌才能实现。在测试的细菌菌株中，几种表现出多重耐药的临床菌株被抑制，这表明PC1针对的是不同的代谢途径。作为原理的证明，我们使用了一个小鼠模型来显示PC1的给药和减少乳腺中金黄色葡萄球菌感染之间的直接关系。这项工作建立了利用现有的结构知识来设计新型的鸟嘌呤核糖开关靶向抗生素作为有效和选择性抗菌化合物的可能性。特别是，这种新的鸟嘌呤核糖开关靶点的发现是至关重要的，因为社区获得性细菌感染最近开始出现。在过去的30年里，细菌对抗生素的耐药性已经成为一个主要问题。造成这种情况的部分原因是，如今的抗生素主要基于有限的化学支架，这使得细菌病原体更容易对新药衍生品迅速产生抗药性。这种反复出现的多重耐药问题意味着需要不断地寻找新的微生物靶标，并使用人造分子来调节它们的活性。核糖开关是新发现的基因调控元件，是抗菌药物的诱人靶点。核糖开关是位于信使RNA的非翻译区的RNA结构，调节与小分子代谢物的运输和代谢有关的基因的表达。我们已经确定了一种新的抗生素，专门针对在包括金黄色葡萄球菌和艰难梭菌在内的一类细菌中发现的核糖开关，这些细菌是医院内导致显著死亡率和医疗成本增加的病原体。核糖开关控制对哺乳动物宿主的毒力至关重要的guaA的表达。一个小鼠模型被用来证明这种抗生素可以抑制哺乳动物体内金黄色葡萄球菌的生长。我们的工作为发现和设计针对细菌病原体的新型抗菌剂提供了新的见解。
Riboswitches are regulatory elements modulating gene expression in response to specific metabolite binding. It has been recently reported that riboswitch agonists may exhibit antimicrobial properties by binding to the riboswitch domain. Guanine riboswitches are involved in the regulation of transport and biosynthesis of purine metabolites, which are critical for the nucleotides cellular pool. Upon guanine binding, these riboswitches stabilize a 5′-untranslated mRNA structure that causes transcription attenuation of the downstream open reading frame. In principle, any agonistic compound targeting a guanine riboswitch could cause gene repression even when the cell is starved for guanine. Antibiotics binding to riboswitches provide novel antimicrobial compounds that can be rationally designed from riboswitch crystal structures. Using this, we have identified a pyrimidine compound (PC1) binding guanine riboswitches that shows bactericidal activity against a subgroup of bacterial species including well-known nosocomial pathogens. This selective bacterial killing is only achieved when guaA, a gene coding for a GMP synthetase, is under the control of the riboswitch. Among the bacterial strains tested, several clinical strains exhibiting multiple drug resistance were inhibited suggesting that PC1 targets a different metabolic pathway. As a proof of principle, we have used a mouse model to show a direct correlation between the administration of PC1 and the reduction of Staphylococcus aureus infection in mammary glands. This work establishes the possibility of using existing structural knowledge to design novel guanine riboswitch-targeting antibiotics as powerful and selective antimicrobial compounds. Particularly, the finding of this new guanine riboswitch target is crucial as community-acquired bacterial infections have recently started to emerge. During the last 30 years, bacterial resistance to antibiotics has become a major problem. This situation is partly because today's antibiotics are mainly based on a limited selection of chemical scaffolds, which makes it easier for bacterial pathogens to quickly develop resistance against new drug derivatives. This recurrent problem of multiple drug resistance implies a constant need to search for novel microbial targets and to modulate their activity using artificial molecules. Riboswitches are newly discovered gene regulatory elements that represent attractive targets for antimicrobial drugs. Riboswitches are RNA structures located in untranslated regions of messenger RNAs that regulate the expression of genes involved in the transport and metabolism of small metabolites. We have identified a new antibiotic specifically targeting riboswitches found in a subgroup of bacteria including Staphylococcus aureus and Clostridium difficile, which are nosocomial pathogens responsible for a significant mortality rate in hospitals, and increased health care costs. The riboswitch controls the expression of guaA that appears essential for virulence in the mammalian host. A murine model was used as a proof of principle to show that such an antibiotic could inhibit the growth of S. aureus in a mammal. Our work provides new insights into the discovery and design of novel antimicrobial agents against bacterial pathogens.
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