The multiple antibiotic resistance (MAR)regulon

多重抗生素耐药性（MAR）调节子

• 批准号: 6693844
• 负责人: STUART B. LEVY
• 金额: $ 46.87万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-30 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693844
• 关键词: multiple; antibiotic; resistance; MAR; regulon

DESCRIPTION (provided by applicant): Multidrug resistance in bacteria has become more the norm than the unusual. While characteristically mediated by plasmids and transposons, increasing evidence shows that chromosomal (intrinsic) regulatory genes and multidrug efflux pumps mediate resistance to multiple antibiotics and hazardous substances. One such regulatory system is the marRAB operon discovered in Escherichia coil whose MarA protein product controls expression of over 80 genes in the mar regulon. Initially described as an activator, MarA appears to have direct repressor activity as well. Homologs of the E.coli MarA and MarR (the repressor of the mar operon) have been found in many different genera including both gram positive and gram-negative organisms. Studies of Salmonella and E.coli reveal not only mar-mediation of drug resistance, but also of colonization and virulence. The DNA binding sites for MarR and MarA have been identified as well as their crystal structures. Still the molecular and biochemical elements which define MarA activation or repression of different genes is not understood, nor is the regulation of the operon by genes other than MarR. To improve knowledge about the molecular control and activity of the mar regulon in E.coli and other clinically important bacteria, this proposal seeks to: 1) determine the molecular basis for the difference between negative and positive transcriptional control by the MarA protein of genes in the mar regulon; studies in vitro and in vivo will define the sequence, orientation and location of the regulatory DNA sequences near the promoters of particular genes in the regulon. 2) enhance understanding of MarR function through two-hybrid studies of its interaction with other proteins, use of macro/micro arrays to determine possible regulation of other loci by MarR, and determination of the crystal structure of MarR with DNA or a ligand. 3) identify other chromosomal genes besides marR that regulate expression of the mar operon. 4) investigate mar loci in other bacteria, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Yersinia pestis. Studies of the E.coli marRAB serve as a paradigm for insights into related genetic loci in other bacteria also of consequence to human health. Improved understanding will help to suggest novel approaches towards preventing and curing infections.

描述（由申请人提供）：细菌中的多药耐药性已成为不寻常的规范。虽然特征是由质粒和转座子介导的，但越来越多的证据表明，染色体（内在的）调节基因和多药外排泵介导对多种抗生素和危险物质的耐药性。这样的调节系统是在大Escherichia卷轴中发现的Marrab操纵子，其MARA蛋白产物控制MAR调节中80多种基因的表达。 Mara最初被描述为激活剂，似乎也具有直接的阻遏活性。在许多不同的属中都发现了大肠杆菌Mara和Marr（Mar Operon的阻遏物）的同源物，包括革兰氏阳性和革兰氏阴性生物。沙门氏菌和大肠杆菌的研究不仅揭示了耐药性的MAR调解，还揭示了定殖和毒力。已鉴定出MARR和MARA的DNA结合位点及其晶体结构。仍然不了解定义MARA激活或抑制不同基因的分子和生化元素，也不了解MARR以外的基因调节操纵子。为了改善对大肠杆菌和其他临床上重要细菌的MAR调节子的分子控制和活性的知识，该提案试图：1）确定MAR Regulon基因Mara蛋白的负转录和阳性转录控制之间差异的分子基础；体外和体内的研究将定义调节基因启动子附近调节DNA序列的序列，方向和位置。 2）通过对MARR与其他蛋白质的相互作用，使用宏/微阵列来确定MARR通过MARR确定其他基因座的可能调节，并确定MARR用DNA或配体确定MARR的晶体结构，从而增强对MARR功能的理解。 3）确定除了调节MAR操纵子表达的MARR以外的其他染色体基因。 4）研究其他细菌中的MAR基因座，包括肺炎克雷伯氏菌，铜绿假单胞菌和鼠疫耶尔森氏菌。大肠杆菌的研究是对其他细菌中相关遗传基因座的见解，这也是对人类健康的影响。改善的理解将有助于提出预防和治愈感染的新方法。