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標題: 利用有關Quorum Sensing 及Quorum Quenching 的Xanthomonas campestris 結構基因體學研究對抗病原菌的嶄新機制
A Novel Strategy for Combating Pathogenic Bacteria by Studying Structural Genomics of Xanthomonas Campestris Regarding Quorum Sensing and Quorum Quenching Mechanism
作者: 周三和
關鍵字: 化學類, 生物技術;商品化
利用有關Quorum Sensing及Quorum Quenching的Xanthomonas campestris結構基因体學研究對抗病原菌的嶄新機制結構基因体, Quorum Sensing, Quorum Quenching, Xanthomonas campestris, 新藥開發目前困擾人類健康最大的問題之一可能就是大多數細菌都已產生抗藥性,所以大部份抗生素都已失去殺菌的功能,在人類受到細菌感染時,無法適時投藥,造成人類健康的一大威脅。雖然世界上各大藥廠持續的研究新藥開發,但是如果沒有開發新的策略,則細菌將一直突變產生抗藥性,人類也始終無法勝過細菌贏得這一場戰役。所以開發新的藥物研發策略,以產生不致或減緩細菌抗藥性產生的新一代藥物,將是廿一世紀生命科學研究人員很大的責任及挑戰。所幸,目前一嶄新的藥物研發策略方式己開始受到重視—即利用破壞細菌Quorum Sensing機制 (所謂Quorum Quenching),來達到破壞細菌的通訊系統,進而避免啟發細菌的致病性。由於細菌有一套分泌訊息分子以判別它們是否已達一定規模,才開始啟動某些致病因子表達的機制。如果破壞了此一通訊機制,細菌將無法開始表達致病因子,也就無法感染人類,而人類的免疫機制就有足夠時間將這些細菌完全消滅。由於此一機制並非直接殺死細菌,故它應不會或可大量減緩細菌產生抗藥性的機會。目前此一嶄新的藥物研發策略已引起廣大注意,並認為可能為廿一世紀人類控制細菌致病的一大秘方。Xanthomonas campestris的Diffusible Signal Factor (DSF)系統為細菌中首先被發現的Quorum Sensing機制,為此一機制的典型系統,在過去十年來已被詳細研究。而此一系統由Regulatory Pathogenic Factor (rpf)基因組形成,包括合成訊息分子的rpfB及rpfF基因, 接受及傳遞訊息的rpfC及rpfG基因,及一些訊息產出的含GGDEF domain的基因。故針對此一基因組的每個蛋白有系統的研究其三度空間結構,並找出其可能的配位子,就有可能研發出最新型的抗菌藥物。本計畫將利用針對Quorum Sensing及Quorum Quenching的結構基因体技術,研究能對抗Xanthomonas campestris的新型藥物。有意思的是,Xanthomonas campestris為感染植物的病原菌,但它與一感染人類的Steinotrophomonus maltophilia有超過97%的序列相似度,而且Steinotrophomonus maltophilia也被證實利用相似的Quorum Sensing系統傳遞信息。故Xanthomonas campestris的Quorum Sensing結構基因体研究將有益於Steinotrophomonus maltophilia的Quorum Sensing研究及新一代藥物的開發。

A Novel Strategy for Combating Pathogenic Bacteria by Studying Structural Genomics of Xanthomonas campestris Regarding Quorum Sensing and Quorum Quenching MechanismStructural Genomics, Quorum Sensing, Quorum Quenching, Xanthomonas campestris, New Strategy for Drug DevelopmentIncidences of antimicrobial-resistant infections have increased dramatically over the past several decades, which have caused considerable threat to the human health. Although development of new antibiotics are being actively pursued by big pharmaceutical companies throughout the world, the drug-resistance issue caused by mutant bacteria will be always present, and human will experience considerable difficulty in combating with bacteria and to win this war due to the drug-resistance prevalence. Therefore an alternative approach toward novel drug development to produce drugs that can eliminate or highly reduce bacterial drug-resistance phenomenon will be the top priority for life science researchers in the 21st century.Fortunately, a novel strategy for such a drug development is emerging now and has been receiving considerable attention in recent years. It utilizes a methodology that destructs the quorum sensing mechanism, which is absolutely necessary for bacteria to communicate with one another and to initiate gene expression of pathogenic factors to infect hosts. By using this sensing mechanism, bacteria can “know” if they have reached to certain critical mass to effectively begin attacking and infecting hosts. Therefore by blocking this important communication system, bacteria will be made “blind” and not be able to launch the pathogenic process. The hosts will then get enough time to begin the immunity system to kill all invading bacteria. Because such a strategy does not aim to kill bacteria directly, it therefore shouldn't generate drug-resistant bacteria or can highly reduce the probability of doing so. This novel strategy has now receiving a great deal of attention and believes to be an excellent way of controlling bacterial infection.The Diffusible Signal Factor (DSF) in Xanthomonas campestris is believed to be the prototype of the quorum sensing mechanism, and has been well studied in the past decade. This system comprises a Regulatory Pathogenic Factor (rpf) gene cluster, including the signal generating genes rpfB and rpfF, receiving and signal tranducing genes rpfC and rpfG, and signal output genes containing various GGDEF-containing domains. By determining the tertiary structures of these proteins, and looking for their ligands, it will be possible to find the next generation anti-bacterial drugs. This proposal thus plans to study the structural genomics of Xanthomonas campestris regarding the quorum sensing and quorum quenching phenomenon, and to discover ligands that can inhibit their functions. It is important to note that although Xanthomonas campestris is a plant pathogen, it bears over 97% sequence identity with Steinotrophomonus maltophilia, an opportunity pathogen that causes considerable hazard to human health. Thus study of Xanthomonas campestris structural genomics shall be helpful for finding useful drugs for Steinotrophomonus maltophilia infection too.
其他識別: NSC99-2113-M005-009-MY3
Appears in Collections:生物化學研究所

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