STRUCTURAL STUDIES ON BETA-LACTAMASE ENZYMES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 β-内酰胺类抗生素是临床上最常见的抗生素，占全球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、单环内酰胺类、青霉烯类和碳青霉烯类，市场上有50多种这类抗生素。细菌对β-内酰胺抗生素的耐药性的主要机制是产生β-内酰胺酶，即在两步过程中水解β-内酰胺的保守四元环的酶。 我们正在研究三种最近发现的β-内酰胺酶。 第一个，命名为GES-1（圭亚那扩展频谱，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-内酰胺酶的亲缘关系很远，对青霉素类和第一代、第二代和一些第三代头孢菌素（如头孢他啶）产生耐药性，但对单环内酰胺类和碳青霉烯类不产生耐药性。 自2000年以来，已经描述了来自不同地理位置的9种GES型酶（GES-1 - GES-9）。 GES酶家族与TEM和SHV超家族的区别最令人担忧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。

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.