CRISPR-Cas9 System-based Gene Editing in the Escherichia coli Genome and Bacterial Drug-resistant Reversal

抗生素的发现是人类对抗病原菌感染的重大里程碑，但是传统抗生素是通过阻断细菌中共有的信号通路或新陈代谢途径来起作用的，往往无法区分杀菌对象，长期使用会导致菌群失调及耐药性的产生，因此我们需要找出一种新型抗菌药物能特异针对病原菌或耐药菌。CRISPR-Cas9系统来源于细菌的获得性免疫，能够利用RNA与Cas相关蛋白识别特异DNA序列并对其进行切割。与传统基因编辑工具如锌指核酸内切酶(ZFNs)和类转录激活因子(TALENs)相比具有简单，高效的优点。因此作为一种新型的基因编辑工具被广泛的应用于各个领域对基因进行改造如敲除，插入和点突变。另一方面，研究人员利用其对基因的特异性识别，从基因水平上识别...The discovery of antibiotic is the great milestone for fighting against the bacterial infection. However, the traditional antibiotic works by blocking conserved bacterial signaling or metabolic pathways, therefore it is unable to distinguish between the pathogen needed to be killed and the bacteria being good for us, Long-termed usage will lead to dysbacteriosis and drug-resistance. We need to fin...学位：医学硕士院系专业：公共卫生学院_转化医学学号：3262014115059

Advances in bacterial drug resistance and new antimicrobial therapy

传统抗生素能够阻断细菌中共有的信号通路或新陈代谢途径,往往无法区分杀菌对象,长期使用会导致菌群失调及耐药性的产生,因此需要找出一种新型抗菌药物能; 特异针对病原菌或耐药菌。本文参阅近年来国内外研究进展,介绍了传统抗生素及细菌产生耐药性的主要机制。并且针对日益严重的细菌耐药性现象而出现的一系列; 新型抗菌疗法进行总结,特别介绍了近年来比较热门的基因编辑工具CRISPR-Cas9系统作为基因特异性杀菌药物的应用。Traditional antibiotics can block conserved bacterial signaling pathway; or metabolic pathway, and therefore it is unable to distinguish; bacteria. Long-termed usage will lead to dysbacteriosis and drug; resistance. We need to find a new antibacterial drug which can target; pathogens and drug-resistant bacteria specifically. By reviewing current; research progress, this paper mainly discussed the mechanisms of; traditional antibiotics and bacterial drug-resistance. We summarized a; series of traditional and new antimicrobial therapies for solving; bacterial drug-resistance, including the application of CRISPR-Cas9; system, a popular gene editing tool, as a gene-specific bactericidal; drug.国家自然科学基金; 福建省自然科学基金; 厦门大学校长基

Advances in bacterial iron homeostasis and antibiotics killing mechanism

传统研究认为不同种类的抗生素有其各自不同的杀菌途径,然而近年人们发现了一条抗生素杀菌的共用通路,那就是当细菌细胞受到抗生素致死性刺激时,呼吸链代谢异常产生大量活性氧簇(ROS),而铁离子对ROS介导的杀菌至关重要。本文参阅近年来国内外研究结果,介绍了铁吸收、储存和利用有关的细菌铁代谢系统及其调控机制,重点讨论铁离子的调控及其与抗生素介导的ROS形成的相互作用关系。对于细菌耐药机制的研究与寻找新型药物作用靶点,探索有效控制手段和开发新药有重要意义。Previous research suggested that different antibiotics kill bacteria via various targets or mechanisms. However, recent study indicated that a common mechanism might be shared by most bactericidal antibiotics. When bacteria suffered lethal stress by antibiotics, reactive oxygen species(ROS) was induced by abnormal respiratory chain reaction in which iron played a key role. By reviewing current research progress regarding antibiotic resistance and iron related proteins in bacteria, including the iron absorbing, storage and consumption system in bacteria, this paper will mainly discuss the possible linkage/interaction between the regulation of ferrous ion and ROS induced by antibiotics. This common bacterial killing mechanism will have a significant impact on the future research for drugresistance, drug target screening, infection controlling and novel drug design.国家自然基金(No.81473251/81301474/31370166);; 福建省自然科学基金(No.2014J01139/2015J01345);; 国家重点基础研究发展计划(973计划)前期研究专项(No.2014CB560710