STRUCTURAL STUDIES ON BETA-LACTAMASE ENZYMES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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耗量的60%以上。它们包括青霉素类、头孢菌素类、单巴西林类、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-内酰胺类抗生素耐药的一个主要机制是产生β-内酰胺酶，这种酶在两步过程中分解保守的四元环的β-内酰胺类抗生素。我们正在研究最近发现的三种β-内酰胺酶。第一种被命名为GES-1(圭亚那扩展光谱，以它最初被分离的国家命名)，最初是在2000年描述的。这种超广谱β-内酰胺酶(ESBL)与其他A类β-内酰胺酶有很远的亲缘关系，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，但对单菌胺类和碳青霉烯类不耐药。自2000年以来，已经描述了来自不同地理位置的9种GES类型的酶(GES-1-GES-9)。GES酶家族最令人震惊的特征是它们不同于TEM超家族和SHV超家族，是它们明显进化成弱碳青霉烯酶的能力，碳青霉烯类抗生素能够水解酶。我们将系统地探索这些系统的结构。

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.