Thienamycin antibacterial activity

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

Since the target enzymes of penicillins are membrane-bound proteins, an essential condition of antibacterial activity is that the antibiotic must be able to penetrate the outer spheres of the bacterial cell and reach its target in an active form. This problem is closely linked to the phenomenon of bacterial resistance (production of /3-lactamases), and justify the development of semisynthetic penicillins varying in the nature of the acylamino side chain at position C-6, and more recently the development of totally synthetic penems related to thienamycin (see Section 2.03.12.3). 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

A synthetic penem-type -lactam (149) exhibited antibacterial activities similar to (+ )-thienamycin (77) (82JA6138). Sulbactam (ISO) showed fairly strong inhibitory activity against /3-Iactamase (78AAC414). Based on the background mentioned above, we developed a new convenient method for the synthesis of penam-type /3-lactams. 

The big surprise concerning the structure of thienamycin is the missing sulfur atom and acylamino side-chain, both of which were thought to be essential to antibacterial activity. Furthermore, the stereochemistry of the side-chain at substituent 6 is opposite from the usual stereochemistry in penicillins. 

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... 

Penems. After oral administration to mice, FCE 22553 (15) and FCE 22891 (16), prodrug esters of FCE 22101, were well absorbed and effective against experimental bacterial infections. Diastereoraeric penems R-Yl and 5-17 exhibited antibacterial activity comparable to thienamycin. ... 

Homocarbapenems with a sulphur (at various oxidation levels) at C-3 were prepared [89] according to a strategy developed earlier for carbapenem synthesis [94]. The key intermediate was the 3-chlorohomocarbapenem 181 (Scheme 52). In spite of their similarity with the thienamycin antibiotics, compounds 182, 184 to 186 exhibit no antibacterial activity. 

The generality of this method is indicated by its recent application in the synthesis of various antibiotics (thienamycin, epithienamy-cin, antibiotics PS-5 and PS-6 333, clavulanic acid,. ..) [83-84]. These new 3-lactam antibiotics display an exceptionally potent and broad-spectrum antibacterial activity against Gram-positive bacteria, including 3-lactamase-producing organisms. 

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