项目来源

台湾省政府科研基金(GRB)

项目主持人

周三和

项目受资助机构

台湾省中兴大学生物化学研究所

财政年度

2012,2011,2010

立项时间

未公开

项目编号

NSC99-2113-M005-009-MY3

项目级别

省级

研究期限

未知 / 未知

受资助金额

7237.00千元台币

学科

化学；生物技术(理)

学科代码

未公开

基金类别

商品化/学术补助

关键词

生化大分子 ; 植物黑腐病菌 ; X-ray绕射蛋白结构 ; 先天免疫 ; Biomolecules ; Xanthomonas campestris ; X-ray crystal structures ; innate immunity

参与者

未公开

参与机构

未公开

项目标书摘要：利用有关Quorum Sensing及Quorum Quenching的Xanthomonas campestris结构基因体学研究对抗病原菌的崭新机制结构基因体,Quorum Sensing,Quorum Quenching,Xanthomonas campestris,新药开发目前困扰人类健康最大的问题之一可能就是大多数细菌都已产生抗药性，所以大部份抗生素都已失去杀菌的功能，在人类受到细菌感染时，无法适时投药，造成人类健康的一大威胁。虽然世界上各大药厂持续的研究新药开发，但是如果没有开发新的策略，则细菌将一直突变产生抗药性，人类也始终无法胜过细菌赢得这一场战役。所以开发新的药物研发策略，以产生不致或减缓细菌抗药性产生的新一代药物，将是廿一世纪生命科学研究人员很大的责任及挑战。所幸，目前一崭新的药物研发策略方式己开始受到重视—即利用破坏细菌Quorum Sensing机制(所谓Quorum Quenching),来达到破坏细菌的通讯系统，进而避免启发细菌的致病性。由於细菌有一套分泌讯息分子以判别它们是否已达一定规模，才开始启动某些致病因子表达的机制。如果破坏了此一通讯机制，细菌将无法开始表达致病因子，也就无法感染人类，而人类的免疫机制就有足够时间将这些细菌完全消灭。由於此一机制并非直接杀死细菌，故它应不会或可大量减缓细菌产生抗药性的机会。目前此一崭新的药物研发策略已引起广大注意，并认为可能为廿一世纪人类控制细菌致病的一大秘方。Xanthomonas campestris的Diffusible Signal Factor(DSF)系统为细菌中首先被发现的Quorum Sensing机制，为此一机制的典型系统，在过去十年来已被详细研究。而此一系统由Regulatory Pathogenic Factor(rpf)基因组形成，包括合成讯息分子的rpfB及rpfF基因，接受及传递讯息的rpfC及rpfG基因，及一些讯息产出的含GGDEF domain的基因。故针对此一基因组的每个蛋白有系统的研究其三度空间结构，并找出其可能的配位子，就有可能研发出最新型的抗菌药物。本计划将利用针对Quorum Sensing及Quorum Quenching的结构基因体技术，研究能对抗Xanthomonas campestris的新型药物。有意思的是,Xanthomonas campestris为感染植物的病原菌，但它与一感染人类的Steinotrophomonus maltophilia有超过97%的序列相似度，而且Steinotrophomonus maltophilia也被证实利用相似的Quorum Sensing系统传递信息。故Xanthomonas campestris的Quorum Sensing结构基因体研究将有益於Steinotrophomonus maltophilia的Quorum Sensing研究及新一代药物的开发。

Application Abstract: A Novel Strategy for Combating Pathogenic Bacteria by Studying Structural Genomics of Xanthomonas campestris Regarding Quorum Sensing and Quorum Quenching Mechanism Structural Genomics,Quorum Sensing,Quorum Quenching,Xanthomonas campestris,New Strategy for Drug Development Incidences 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.

项目受资助省

台湾省