Thienamycin from Streptomyces cattleya

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

Imipenem Imipenem, [5R-[5a,6a(R)]]-6-(l-hydroxyethyl)-3-[[2-[(iminomethyl)amino] ethyl]thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-en-2-carboxyUc acid (32.1.3.1), is the only car-bapenem presently used in clinics. It is synthesized from thienamycin isolated from Streptomyces cattleya by reacting it with the methyl formimidate [179-182]. 

The search continues for the ideal beta-lactam antibiotic, and numerous esoteric substances have been isolated from natural sources or have been synthesised during the past 15 years. These include the penems, carbapen-ems, cephamycins, monobactams, etc. The penems are wholly synthetic and from a clinical viewpoint have not been successful, while more success has been obtained with the carbapenems, which include the natural product thienamycin (from Streptomyces cattleya) and the analogues imipenem and meropenem. These carbapenems have a remarkable spectrum of antibacterial activity with a very high activity against pseudomonads. Thienamycin is relatively unstable, but the addition of a formamidine group to produce... 

Thienamycin, the first of the carbapenems, was isolated from Streptomyces cattleya. Because of its extremely intense and broad-spectrum antimicrobial activity as well as its ability to inactivate (3-lactamases, it combines in one molecule the functional features of the best of the (3-lactam antibiotics as well as the (3-lactamase inhibitors. It differs structurally in several important respects from the penicillins and cephalosporins. The sulfur atom is not part of the 5-membered ring but, rather, has been replaced by a methylene moiety at that position. Carbon is roughly half the molecular size of sulfur. Consequently, the carbapenem ring system is highly strained and very susceptible to reactions cleaving the (3-lactam bond. The sulfur atom is now attached to C-3 as part of a functionalized side chain. 

Independently of the work on the olivanic acids, researchers at the Merck Company had isolated, and determined the structure of, the related compound thienamycin (107) produced by Streptomyces cattleya 80,81). Here a free amino group is present, while the configuration at C(8) is R). An extensive review of all aspects of the chemistry of thienamycin has recently been published (103). Two derivatives of thienamycin found in the same fermentation broth were iV-acetyl thienamycin (108) (81, 82) and N-acetyldehydro-thienamycin (109) (81, 83). Workers at Merck have also isolated from Streptomyces flavogriseus various epithienamycins (A to F), which correspond to the olivanic acids (77). Subsequently discovered by numerous Japanese workers were PS-5 (110) (85,86), carpetimycin A (111) (90,91), asparenomycin A (112) (92) and the many other compounds listed in Table 5. 

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