Erythromycin chemical modification

Figure 12 Macrolide modifying enzymes. Macrolide antibiotics such as erythromycin (shown) bind to the large ribosomal subunit through interactions with the 23 S rRNA (A). Chemical modification of the essential desosamine sugar blocks ribosome binding (B).

Fig. 2. The peptidyltransferase center. The structure of the central loop of Domain V of E. coli 23S rRNA is shown. Nucleotides involved in resistance against different inhibitors are indicated. Closed symbols indicate resistance and open symbols protection against chemical modification by bound antibiotic. Mutations that confer resistance to anisomycin in archaea are indicated [87] (Hcu, Halobacterium cutirubrum Hha, H. halobium). The presence of either a G or U at position 2058 in archaea is also indicated. As a consequence of this change archaea are resistant to erythromycin (Hmo, Halococcus morrhuae, Mva, Methanococcus vannielii Tte, Thermoproteus lenax Dmo, Desulfurococcus wofirfo) [29,30,88,90]. Positions where crosslinking to photoreactive derivatives of Phe-tRNA and puromycin have been observed as well as nucleotides protected by bound tRNA are also indicated. Modified from ref [73].

Morimoto, S., Takahashi, Y, Watanabe, Y, Omura, S. Chemical modification of erythromycins. 1. Synthesis and antibacterial activity of 6-O-methylerythromycins A. J. Antibiot. (Tokyo) 1984, 37, 187-189. 

Nishida. A.. Yagi, K., Kawahara, N., Nishida, M., and Yonemitsu, ()., Chemical modification of erythromycin A. Synthesis of the C1-C9 fragment from erythromycin A and reconstruction of the macrolactone ring. Tetrahedron Lett., 36, 3215, 1995. 

This chapter deals with recent progress in the chemical modification and structure-activity relationships of 14- and 15-membered macrolides (mainly erythromycin derivatives), 16-membered macrolides (mainly the leucomycin and tylosin families), and the avermectin family of macrolides, showing nematocidal, insecticidal, and arachnidicidal activities. Previous reviews of these macrolides were given by Sakakibara and Omura in the first edition of this book in 1984 [1]. 

Gasc, J.-C., D Ambrieres, S, G, Lutz, A., and Chantot, J. R (1991). New ether oxime derivatives of erythromycin A. A structure-activity relationship study. J. Antibiot. 44, 313-330. Morimoto, S., Takahashi, Y., Watanabe, Y, and Omura, S. (1984). Chemical modification of erythromycins. 1. Synthesis and antibacterial activity of 6-0-methylerythromycins A. J. Antibiot. 37, 187-189. 

The first research project that Alex undertook in the Institute was directed to the chemistry of the macrolide anitibiotic, erythromycin. Chemical modifications led to a new derivative, 8-hydroxyerythromycin, a patent on which was purchased by a major pharmaceutical company. At the same time, Alex initiated studies on the total synthesis of monosaccharides via the Diels-Alder adduct of... 

Although recent advances in total synthesis are now approaching feasibility for structure-activity studies, chemical modification of erythromycin is still the most practical route for the synthesis of derivatives, since the starting material is readily available from fermentation sources. All of the commercially available derivatives of erythromycin as well as those in various stages of development are semi-synthetic products. The rationale for synthesis of many of these derivatives has been largely influenced by the mechanism of decomposition of erythromycin. 

Martin YC, Jones PH, Perun TJ, Grundy WE, Bell S, Bower RR, Shipkowitz NL (1972) Chemical modification of erythromycin antibiotics. 4. Structure-activity relations of erythromycin esters. J Med Chem 15 635-638... 

One of the most important groups of secondary products used in the treatment of diseases are the antibiotics (E 5.2) of which some 100 products are on the market. In 1980 worldwide antibiotic production was estimated at about 25,000 tons, including 17,000 tons of penicillins (D 23.3), 5,000 tons of tetracyclines (D 3.3.7), 1,200 tons of cephalosporins (D 23.3) and 800 tons of erythromycins (D 4). The search for new antibiotics continues because of the development of new resistant strains and the need for cheaper, safer, and more active products. Chemical modification of natural antibiotics is of increasing significance in this respect. Antibiotics are not only used in human or veterinary medicine, but on a large scale also for growth promotion of farm animals. 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

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