Regulation/mecA gene expression/clinic S.aureus isolates

调控/mecA 基因表达/临床金黄色葡萄球菌分离株

• 批准号: 6945806
• 负责人: ADRIANA E ROSATO
• 金额: $ 10.8万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945806
• 关键词: Staphylococcus aureus; bacterial genetics; biochemical evolution; biological signal transduction; cytogenetics; cytotoxicity; drug resistance; gene expression; gene induction /repression; genetic regulation; genetic regulatory element; methicillin; microarray technology; nucleic acid hybridization; nucleic acid sequence

DESCRIPTION (provided by applicant): One of the most serious contemporary challenges to the treatment of hospital-acquired infections worldwide is the appearance and global spread of staphylococci resistant to all beta-lactam antibiotics (known as methicillin-resistant S. aureus; MRSA). Staphylococci can become resistant to Beta-lactam antibiotics by acquiring a gene (mecA) that encodes a beta-lactam insensitive target enzyme, penicillin binding protein (PBP)2a. This enzyme affords the bacterium the ability to cross-link cell wall and grow while the cell's usual cross-linking enzymes (PBP's) are bound and inactivated by Beta-lactam antibiotics. Most of S. aureus also produce/beta-lactamase encoded by blaZ, which can hydrolyse Beta-lactam antibiotics rendering them inactive. The transcription of mecA and blaZ is regulated by related divergently transcribed two-gene operons mecRl-mecI and blaRl-blaI, respectively that encode a signal transducer (R1) and a repressor (I). The ongoing studies outlined in this proposal are based on previous observations in laboratory strains that demonstrated the coregulation of mecA by both MecI and BlaI Furthermore, these observations could be extended to clinically relevant isolates which escape MecI repression in order to survive/beta-lactam pressure (36). The goal of this proposal is to provide evidence of the existence of additional loci involved in or required for inducible expression of methicillin resistance. These data will provide valuable structure/function information to complement studies investigating the molecular basis of MecR1/BlaR1 and MecI/BlaI signal transduction. The specific aims are: To Investigate the molecular basis of signal transduction through MecR1/BlaR1 to MecI/Blalby identifying and characterizing "mecR2" loci - chromosomal genes that may contribute to the induction of mecA/blaZ expression. To test the hypothesis that repression is evolutionarily conserved in order to prevent overproduction of a toxic, regulated gene product. Specifically, we will evaluate if the inducible overexpression of either MecR1/BlaR1 or their corresponding mutants/deletants in the absence of Beta-lactam induction results in a toxic effect to the cell.

描述（由申请人提供）：当今世界范围内医院获得性感染治疗面临的最严峻挑战之一是对所有 β-内酰胺类抗生素具有耐药性的葡萄球菌（称为耐甲氧西林金黄色葡萄球菌；MRSA）的出现和全球传播。 。葡萄球菌可以通过获得编码 β-内酰胺不敏感靶酶、青霉素结合蛋白 (PBP)2a 的基因 (mecA) 而对 β-内酰胺抗生素产生耐药性。这种酶使细菌能够交联细胞壁并生长，而细胞的常用交联酶 (PBP) 会被 β-内酰胺抗生素结合并失活。大多数金黄色葡萄球菌还产生 blaZ 编码的 β-内酰胺酶，它可以水解 β-内酰胺抗生素，使其失去活性。 mecA 和 blaZ 的转录受到相关的不同转录的双基因操纵子 mecR1-mecI 和 blaR1-blaI 的调节，分别编码信号转导子 (R1) 和阻遏子 (I)。本提案中概述的正在进行的研究基于先前对实验室菌株的观察，这些观察证明了 MecI 和 BlaI 对 mecA 的共同调节。此外，这些观察结果可以扩展到逃避 MecI 抑制以生存/β-内酰胺压力的临床相关分离株(36)。该提案的目的是提供证据，证明存在与甲氧西林耐药性的诱导表达有关或所需的其他基因座。这些数据将提供有价值的结构/功能信息，以补充研究 MecR1/BlaR1 和 MecI/BlaI 信号转导的分子基础。具体目标是： 研究通过 MecR1/BlaR1 到 MecI/Blal 的信号转导的分子基础，通过识别和表征“mecR2”基因座 - 可能有助于诱导 mecA/blaZ 表达的染色体基因。检验抑制在进化上是保守的这一假设，以防止有毒的、受调控的基因产物的过量产生。具体来说，我们将评估在缺乏 β-内酰胺诱导的情况下 MecR1/BlaR1 或其相应突变体/缺失体的诱导性过度表达是否会对细胞产生毒性作用。

项目成果

Staphylococcus aureus as an infectious agent: overview of biochemistry and molecular genetics of its pathogenicity.

金黄色葡萄球菌作为传染原：其致病性的生物化学和分子遗传学概述。

• DOI: 10.18388/abp.2009_2491
• 发表时间: 2024-09-14
• 期刊: Acta biochimica Polonica
• 影响因子: 1.7
• 作者: Konrad B. Plata;A. Rosato;G. Węgrzyn
• 通讯作者: G. Węgrzyn

Identification and phenotypic characterization of a beta-lactam-dependent, methicillin-resistant Staphylococcus aureus strain.

β-内酰胺依赖性、耐甲氧西林金黄色葡萄球菌菌株的鉴定和表型特征。

• 发表时间: 2007-07
• 影响因子: 4.9
• 作者: Goldstein, Fred;Perutka, Jiri;Cuirolo, Arabela;Plata, Konrad;Faccone, Diego;Morris, Joanne;Sournia, Aude;Kitzis, Marie Dominique;Ly, Aicha;Archer, Gordon;Rosato, Adriana E
• 通讯作者: Rosato, Adriana E

Unusual form of oxacillin resistance in methicillin-resistant Staphylococcus aureus clinical strains.

耐甲氧西林金黄色葡萄球菌临床菌株中苯唑西林耐药的异常形式。

• 发表时间: 2008-08
• 影响因子: 2.9
• 作者: Forbes, Betty A;Bombicino, Karina;Plata, Konrad;Cuirolo, Arabela;Webber, Dawn;Bender, Connie L;Rosato, Adriana E
• 通讯作者: Rosato, Adriana E

Development of homogeneous expression of resistance in methicillin-resistant Staphylococcus aureus clinical strains is functionally associated with a beta-lactam-mediated SOS response.

耐甲氧西林金黄色葡萄球菌临床菌株中耐药性同质表达的发展与 β-内酰胺介导的 SOS 反应在功能上相关。

• DOI: 10.1093/jac/dkp164
• 发表时间: 2009-07-01
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: A. Cuirolo;Konrad B. Plata;A. Rosato
• 通讯作者: A. Rosato