Thienamycin

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Thienamycin is a novel β-lactam antibiotic first isolated andidentified by researchers at Merck from fermentation ofcultures of Streptomyces cattleya. Its structure and absoluteconfiguration were established both spectroscopically and bytotal synthesis. Two structural features of thienamycinare shared with the penicillins and cephalosporins: a fusedbicyclic ring system containing a β-lactam and an equivalentlyattached 3-carboxyl group. In other respects, the thienamycinsrepresent a significant departure from the establishedβ-lactam antibiotics. The bicyclic system consists of a carbapenemcontaining a double bond between C-2 and C-3(i.e., it is a 2-carbapenem, or 2-carbapenem, system). Thedouble bond in the bicyclic structure creates considerablering strain and increases the reactivity of the β-lactam to ringopeningreactions.Thienamycin displays outstanding broad-spectrum antibacterialproperties in vitro. It is highly active againstmost aerobic and anaerobic Gram-positive and Gramnegativebacteria, including S. aureus, P. aeruginosa, andB. fragilis. Furthermore, it is resistant to inactivation bymost β-lactamases elaborated by Gram-negative and Grampositivebacteria and, therefore, is effective against manystrains resistant to penicillins and cephalosporins. Resistanceto lactamases appears to be a function of the β-1-hydroxyethyl side chain because this property is lost in the6-nor derivative and epithienamycins with S stereochemistryshow variable resistance to the different β-lactamases.An unfortunate property of thienamycin is its chemical instabilityin solution. It is more susceptible to hydrolysis inboth acidic and alkaline solutions than most β-lactam antibiotics,because of the strained nature of its fused ring systemcontaining an endocyclic double bond. Furthermore, at itsoptimally stable pH between 6 and 7, thienamycin undergoesconcentration-dependent inactivation. This inactivation isbelieved to result from intermolecular aminolysis of the β-lactam by the cysteamine side chain of a second molecule.Another shortcoming is its susceptibility to hydrolytic inactivationby renal dehydropeptidase-I (DHP-I),62 whichcauses it to have an unacceptably short half-life in vivo.