STRUCTURAL STUDIES ON BETA-LACTAMASE ENZYMES

β-内酰胺酶的结构研究

• 批准号: 8362079
• 负责人: CLYDE A SMITH
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362079
• 关键词: Antibiotics; Carbapenems; Ceftazidime; Cephalosporins; Characteristics; Clinical; Consumption; Country; Enzymes; Family; First Name; Funding; Generations; Geographic Locations; Grant; Marketing; Monobactams; National Center for Research Resources; Penicillin Resistance; Penicillins; Principal Investigator; Process; Production; Radiation; Research; Research Infrastructure; Resources; Source; Structure; System; United States National Institutes of Health; Work; antimicrobial drug; bacterial resistance; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; cost; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Beta-lactams are the most common antibiotics in clinical use and represent more than 60% of total world consumption of antimicrobial drugs. They include penicillins, cephalosporins, monobactams, penems and carbapenems, and over 50 antibiotics of this class are available on the market. A major mechanism of bacterial resistance to beta-lactam antibiotics is the production of beta-lactamases, enzymes that hydrolyze the conserved four-membered ring of beta -lactams in a two-step process. We are working on three recently-discovered beta -lactamase enzymes. The first, named GES-1 (Guiana Extended-Spectrum, after the country where it was first isolated) was initially described in 2000. This extended spectrum beta -lactamase (ESBL) is very distantly related to other class A beta -lactamases and produces resistance to penicillins and first-, second-, and some third-generation cephalosporins (e.g. ceftazidime) but not to monobactams and carbapenems. Since 2000, nine GES-type enzymes (GES-1 - GES-9) from different geographical locations have been described. The most alarming characteristic of the GES family of enzymes that distinguish them from the TEM and SHV superfamilies, is their apparent ability to evolve into weak carbapenemases, enzymes capable of hydrolyzing carbapenem antibiotics. We will systematically pursue structures of these systems.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 β-内酰胺类是临床上最常用的抗生素，占世界抗菌药物总消费量的 60% 以上。它们包括青霉素类、头孢菌素类、单菌素类、青霉烯类和碳青霉烯类，市场上有超过 50 种此类抗生素。细菌对β-内酰胺抗生素耐药的一个主要机制是产生β-内酰胺酶，这种酶通过两步过程水解β-内酰胺的保守四元环。 我们正在研究三种最近发现的 β-内酰胺酶。 第一个被命名为 GES-1（圭亚那超广谱，以其首次分离的国家命名）最初于 2000 年描述。这种超广谱 β-内酰胺酶 (ESBL) 与其他 A 类 β-内酰胺酶关系非常远，并产生对青霉素和第一代、第二代和某些第三代头孢菌素（例如头孢他啶）有耐药性，但对单环菌素和碳青霉烯类。 自 2000 年以来，来自不同地理位置的九种 GES 型酶 (GES-1 - GES-9) 已被描述。 GES 酶家族与 TEM 和 SHV 超家族的最令人震惊的特征是它们明显能够进化成弱碳青霉烯酶，即能够水解碳青霉烯类抗生素的酶。 我们将系统地研究这些系统的结构。