Cephamycin antibiotics

Acylation of amide bonds in peptides can be accomplished by silylation with trimethylsilyl chloride followed by treatment with acid chlorides. A modified procedure has been applied to acylation of the sensitive 3-lactam antibiotic cephamycin, where silylamides like trimethylsilylurethane trap generated HCl (equation 54). ... 

Cefoxitin contains the same C-7 side chain as cephaiothin and the same C-3 side chain as cefuroxime. The most novei chemicai feature of cefoxitin is the possession of an a-oriented methoxyl group in place of the normai H-atom at C-7. This increased steric buik conveys very significant stability against (3-lactamases. The inspiration for these functionai groups was provided by the discovery of the naturally occurring antibiotic cephamycin C... 

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomjces species have been shown to produce carbapenems, only S. cattkja (2) and S. penemfaciens (11) have been reported to give thienamycin (2). Generally the antibiotics occur as a mixture of analogues or isomers and are often co-produced with penicillin N and cephamycin C. Yields are low compared to other P-lactams produced by streptomycetes, and titres are of the order of 1—20 p-g sohdusmL despite, in many cases, a great deal of effort on the optimization of the media and fermentation conditions. The rather poor stabiUty of the compounds also contributes to a low recovery in the isolation procedures. The fermentation and isolation processes for thienamycin and the olivanic acids has been reviewed in some detail (12). 

Fermentation. The commercial P-lactam antibiotics which act as starting material for all of the cephalosporins ate produced by submerged fermentation. The organisms used for the commercial production of the penicillins and cephalosporins ate mutants of PenicU/in chTysogenum and Cephalosporium acremonium respectively (3,153,154). Both ate tme fungi (eucaryotes). In contrast, the cephamycins ate produced by certain species of procaryotic Streptomyces including Streptomyces clavuligerus and Streptomyces lipmanii (21,103). 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

The ribosome-associated ppGpp synthetase (RelA) is required for antibiotic production under the conditions of nitrogen limitation in S. coelicolor A3 and for cephamycin C production in S. clavuligerus. Deletion of the relA in S. coelicolor A3 results in the loss of production of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red) and... 

Enzymatic inactivation or modification of antibiotics has been discussed by many authors [179-182, 186-188], As described earlier, /(-lactams may be susceptible to /(-lactamases. During the past 30-odd years, several -lactams have been synthesized that are less susceptible to these enzymes. Such drugs include (i) newer types of /(-lactam structures, e.g. carbapenems (37), cephamycins (40) and carbacephems (53), and (ii) modifications of the side-chains of existing penams (38) or cephems (39) [317]. Nevertheless, the wide diversity of /(-lactamases [180,181,318] means that organisms producing enzymes with broad-spectrum activity may be able to resist some members of the /(-lactam group, /(-lactamase inhibitors such as clavulanic acid (36), and the penicillanic acid sulphone (54) derivatives, tazobactam (55) and sulbactam (56) have been combined with, and protect, appropriate /(-lactamase-susceptible penicillins, with useful clinical results. Most extended-spectrum /(-lactamases are susceptible to these inhibitors, but newer -lactamase inhibitors may still be needed. 

The second major group of P-lactam antibiotics includes cephalosporins and cephamycins. The analog X is H are cephalosporins, and those X is OCH3 are called cephamycins. 

One approach has been to modify the structure of the yS-lactam antibiotic so as to increase its stability and thus confer resistance to yS-lactamases, whilst retaining its inhibitory activity against transpeptidases. This was achieved by introducing sterically crowded 6-acyl substituents, as in methicillin (1) and the isoxazolyl penicillins (2) and (3) [20], or by the introduction of a methoxy substituent to the a-face of the -lactam, as in cefoxitin (9) [21] and temocillin (11) [22]. The two latter compounds were a direct result of the discovery of the y5-lactamase stable cephamycins (10), isolated by fermentation of Streptomyces in 1970 by Merck and Lilly [23]. 

Cephalosporins were first obtained from a filamentous fungus Cephalosporium cultured from the sea near a Sardinian sewage outfall in 1945 their molecular structure is closely related to that of penicillin, and many semisynthetic forms have been introduced. They now comprise a group of antibiotics having a wide range of activity and low toxicity. The term cephalosporins will be used here in a general sense although some are strictly cephamycins, e.g. cefoxitin and cefotetan. 

Cephamycins include p-lactam such as cefoxitin, cefotetan, cefmetazole and latamoxef (moxalactam). Cephamycins are active against anaerobic bacteria, are less active against gram-positive cocci and, have no activity against methicillin-resistant staphylococci and enterococci. Cephamycin antibiotics such as cefotetan and latamoxef have a side chain called the... 

Since it is a zwitterion, cephalosporin C can also be adsorbed on low cross-linked sulfonic acid cation exchange resins, as shown in Figure 5, Although used successfully for cephamycin C (15), a related 8-lactam antibiotic, the strong acidity of these resins results in substantial degradation of cephalosporin C to its lactone. (Cephamycin C contains a carbamoyl ester in place of the acetyl ester at C-3, and is apparently more stable.) Elution of the adsorbed cephalosporin C with acetate buffers yields eluates with high lactone content. 

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... 

However, by far the most important strategy involves the production of enzymes that destroy or deactivate the antibiotics. Bacterial enzymes that inactivate chloramphenicol (e.g., chloramphenicol acetyl transferase) and the aminoglycosides (usually enzymes that acetylate or phosphorylate the aminoglycosides) are quite common, but it is the penicillinases or, as they are now called, the beta-lactamases, that have had the most impact on antibacterial chemotherapy. The beta-lactam antibiotics, including the penicillins, cephalosporins and the newer variants called penems, carbapen-ems, cephamycins and monobactams, all possess the four-membered ring... 

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