This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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