A new //-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition CuHIGN2O4S (M.W.=272.18) and possesses a distinctive UV absorption (Amax=297 nm, e=7,900). Its /3-lactam is unusually sensitive to hydrolysis above pH 8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations. * This report was presented in part at the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 1976 (q. v. abstract #227) ** This antibiotic is the first representative of a family of des-thia-carbapenem nucleus antibiotics in which the enamine portion of the fused 5-member ring bears a thioethylamine moiety. From this structural feature , the name thienamycin (thi'en-a-mi'san) is derived. THE JOURNAL OF ANTIBIOTICS JAN.
The avermectins, a family of new anthelmintic agents, were isolated from the mycelia of Streptomyces avermitilis. Four closely related major components and four homologous minor components were separated from the complex. Solvent extraction, solvent partition, and adsorption methods were used to isolate and purify the complex; novel partition chromatography systems using Sephadex LH-20 were used to separate the components. A reverse-phase high-pressure liquid chromatography assay for the quantitative determination of all components was used extensively to monitor the purification methods.The avernectin complex, a family of new anthelmintic agents, is produced by fermentation of Streptomyces avermitilis (NRRL 8165), as described in a separate publication (1).The complex contains four closely related major components, Ala, A2a, Bia, and B2a, in varying proportions and four minor components, Alb, A2b, Blb, and B2b, each of which is a lower homolog ofthe corresponding major component. The structures and physicochemical properties of all components are the subject of a separate publication (G. Soc., in press).In this report, the isolation of the complex from broth, the separation of all of its components, and the chromatographic properties of each will be described. For the sake of simplicity, mixtures of homologs will be designated by omis- B2a, 6.74; A2b, 7.22; A2s, 8.00; B,I, 8.32; B,I., 9.70; Al,b, 11.06; and A,,, 11.78. The UV monitor was set at 246 nm to improve the resolution of a major impurity which exhibited a UV maximum at a lower wavelength. Although the UV maximum for avermectins occurred at 245 nm, sensitivity was only slightly reduced at 246 nm, whereas the sensitivity for the impurity was reduced substantially. The UV spectrum of B21 is given in Fig. 1 and is characteristic of all components. Recordings of high-pressure liquid chromatography (HPLC) assays of standard and unknown solutions are given in Fig. 2. RESULTSIsolation of avermectin complex. Approximately 8,000 liters of fermentation broth was filtered, and the cake was washed with water. The wet cake was then slurried in 3,000 liters of acetone, filtered, and washed with 400 liters of 80% acetone. The cake was discarded, and the combined extract and wash were concentrated to 800 liters. The concentrate was adjusted to pH 5 with dilute HCl and then extracted twice with 800-liter portions of methylene chloride.
Dehydropeptidase I catalyzed hydrolysis of the carbapenem antibiotics imipenem (1) and the 3-methylthio analogue 14 was examined by spectroscopic methods. The principal product in both cmes was a mixture of p-lactam ring-opened 1-pyrrolines epimeric a t C3. A transient 2-pyrroline intermediate was observed by 'H NMR in the methylthio carbapenem case. Nonenzymatic acid-catalyzed hydrolysis of each antibiotic under dilute conditions rapidly afforded a protonated 2-pyrroline product that isomerized to the diastereomeric 1-pyrroline mixture on neutralization. At higher carbapenem concentrations, the acid-catalyzed process also produced a diketopiperazine structure resulting from initial bimolecular attack of the carboxyl group of one carbapenem molecule on the p-lactam group of a second molecule. The analysis of the imipenem-derived products was complicated by the observation of side-chain formamidinium rotational isomers. Under mildly acidic conditions, the imipenem side-chain isomers were separable by high pressure liquid chromatography and the major form was identified as the 2 isomer by X-ray crystallography. (6) (a) Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.; Chen, A.; Graham, D. W.; Kahan, K. M.; Kropp, H.; Sundelof, J. G.; Rogers, E.
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