Erythromycin biological activity

Pacey, M.S., Dirlam, J.P., Geldart, R.W. et al. (1998) Novel erythromycins from a recombinant Saccharopolyspora erythraea strain NRRL 2338 pIGl. I. Fermentation, isolation and biological activity. The Journal of Antibiotics, 51, 1029. 

In many cases, biotechnology-derived products may have many components that have biological activity. The aim should be to devise controls that monitor the various components so as to retain a consistent potency and purity. For example, the USP monograph for erythromycin [9] indicates that the principal component is erythromycin A and that the percentage of erythromycin A, erythromycin B, and erythromycin C is not less than 85.0% and not more than 100.5%. Within these parameters, the relative ratios of erythromycins A, B, and C may change. This is not always the case for biotechnology-derived products, however. For example, the USP monograph for amoxicillin [10] allows for only one active component. 

Second, many macrocycles possess biological activities, that are unrivaled by more traditional small ring medicinal compounds. This combination of high activity and especially selectivity gives macrocycles an enormous potential in drug development, which is illustrated by the great importance of the macrolide antibiotics such as erythromycin or vancomycin for the treat-... 

Erythromycin and azithromycin are excreted primarily in active form in bile, with only low levels found in urine. Clarithromycin is metabolized to the biologically active 14-OH metabolite and is eliminated largely by the kidney. The half-life of erythromycin is approximately 1.4 hours, whereas the half-life of clarithromycin is 3 to 7 hours and that of azithromycin approaches 68 hours. 

Kosan Biosciences was formed almost 6 years ago, founded on an interest in polyketides, microbial metabolite-based drugs. Polyketides have many diverse chemical structures including erythromycin, which will be mentioned again later. These chemicals include fused-ring aromatic compounds, compounds decorated with sugars, and compounds with large stretches of double bonds. Each of these compounds has different biological activities and utilities, but they are all made in nature by very similar biochemistry. 

Figure 2 Examples of polyketides. Polyketides demonstrate a broad range of biological activities, including antibiotic (oxytetracycline and erythromycin), antitumor (doxorubicin and dynemicin), antiparasitic (avermectin), and immunosuppressive (FK506). Monensin is used as a bovine feed supplement and an anticoccidial agent.

More than 500 different representatives of the macrolide antibiotics are known, most of which are biologically active against Gram-positive bacteria, displaying a relatively low toxicity. Clinically used are erythromycin, oleandomycin, carbomycin and leucomycin (O Fig. 5). They act as inhibitors of the bacterial protein biosynthesis by binding to the 50S-ribosomal subunit. The synthesis of the two clinically important 16-membered ring macrolide antibiotics leucomycin A3 and carbomycin B could be started from D-glucose, which was chosen because it contained three of the required stereocenters [40]. 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

The anti-bacterial activity of the penicillins stimulated a major search for other antibiotics. Many compounds were isolated from amongst the metabolites of Streptomycetes obtained from soil. These included therapeutically useful antibiotics such as chloramphenicol, the tetracyclines, erythromycin and streptomycin. Several fungi yielded useful compounds. One of these was Cephalosporium acremonium. A biologically-active strain was obtained by Brotzu from a sewage outfall near Cagliari in Sardinia in 1945 and described in 1946. The p-lactam cephalosporin C (1.23) was isolated from this organism in 1954 and its structure determined in 1961 by Abraham and Newton. 

Under acidic conditions erythromycin can undergo spontaneous intramolecular ring cy-clizations, the products of which are inactive (96-99). All contain either the 6,9-hemiketal or the 8,9-anhydro-6,9-hemiketal they may also contain the 6,9 9,12-spiroketal. The synthesis and isolation of the biologically active... 

Baker, W. R., Fernandes, P. B., Bopp, B., Marsh, K., Nellans, H., Clark, J., Herrin, T., and Hannick, S. (1987). Synthesis and biological activity of erythromycin A 11,12-cyclic carbamates. Presented at 27th Intersci. Conf. Antimicrob. Agents Chemother (Oct. 4-7, New York). Abstr. No. 221. 

Kondo, Y, Torii, K., Omura, S., and Itoh, Z. (1988). Erythromycin and its derivatives with motilin-like biological activities inhibit the specific binding of 1251-motilin to duodenal muscle. Biochem. Biophys. Res. Commun. 150, 877-882. 

Sato, K., Suga, M., Nishimura, J., Kushima, Y, Muranaka, H., and Ando, M. (1997). Pyocyanine synthesis by Pseudomonas aeruginosa in chronic airway infection and the effect of erythromycin on its biological activity. Jpn. J. Antibiot. 50 (Suppl.), 89-91. 

There are many examples of important biologically active molecules formed by polyketide biosynthesis. Aureomycin and terramycin (Section 21.2) are examples of other aromatic polyketide antibiotics. Erythromycin (Section 17.7C) and aflatoxin, a carcinogen (see Why do these topics matter in Chapter 14), are polyketides from other pathways. 

Miller and co-workers reported a seminal work in the field of site-selective functionalization of biologically active polyol natural products by non-enzymatic protocol (Fig. 10). They reported that acylation of a polyol macrolide antibiotic, erythromycin A, took place first at C(2 )-OH and second at C(4")-OH by treatment with 2.0 equiv. of acetic anhydride in the presence of iV-methyl imidazole. These two hydroxy groups seem to be intrinsically most reactive. On the other hand, the second acylation took place at C(ll)-OH selectively when peptide-based catalysts 32 was used (Fig. 10) [36]. Thus, catalyst-controlled reversal of the site-selectivity in the acylation of biological active polyol natural products was achieved for the first time by non-enzymatic protocol. This strategy was further applied to site-selective diversification of apoptolidin A with antitumor activity [37]. 

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