STRUCTURAL STUDIES ON GES-1

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。60多年来，抗生素的广泛使用，有时甚至是无节制的使用，导致了耐药微生物的选择和在世界范围内的传播，这对传染病的抗生素治疗构成了严重威胁。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，这种酶能分解保守的四元环的β-内酰胺类药物，使它们失去活性。第一个GES(圭亚那扩展光谱；以第一个分离物的原产国命名)β-内酰胺酶，GES-1于2000年被描述。这种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-第二代头孢菌素以及一些第三代头孢菌素(例如。头孢他啶)，但对单菌胺和碳青霉烯类不适用。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。肺炎克雷伯菌A类超广谱β-内酰胺酶GES-1的结构已测定到1.1A分辨率。GES-1具有碳青霉烯酶家族β-内酰胺酶家族特有的活性部位二硫键，其结构与其他已知的碳青霉烯酶非常相似，包括NMC-A、SME-1和KPC-2。我们还用亚胺培南、克拉维酸、他唑巴坦和舒巴坦等抑制剂浸泡在活性中心，解决了GES-1的结构问题。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. Over 60 years of extensive and sometimes uncontrolled use of antibiotics has resulted in selection and world-wide spread of resistant microorganisms, and this poses a serious threat to the antibiotic therapy of infectious diseases. 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, rendering them inactive. The first GES (Guiana Extended-Spectrum; named after the country of origin of first isolate) beta-lactamase, GES-1 was described in 2000. This ESBL is very distantly related to other class A beta-lactamases and produces resistance to penicillins and first- second-, and some third-generation cephalosporins (eg. 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. The structure of the class A extended-spectrum beta-lactamase GES-1 from Klebsiella pneumoniae has been determined to 1.1 A resolution. GES-1 has the characteristic active site disulfide bond of the carbapenemase family of beta-lactamases, and has a structure very similar to other known carbapenemases, including NMC-A, SME-1 and KPC-2. We have also solved the structures of GES-1 with the inhibitors imipenem, clavulanic acid, tazobactam and sulbactam soaked into the active site.