Medicines Macrolides

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

Katz, L. and McDaniel, R. (1999) Novel macrolides through genetic engineering. Medicinal Research Reviews, 19, 543. 

Hoerauf, A., Volkmann, L., Nissen-Paehle, K., Schmetz, C., Autenrieth, I., Buttner, D.W. and Fleischer, B. (2000b) Targeting of Wolbachia endobacteria in Litomosoides sigmodontis comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin. Tropical Medicine and International Health 5, 275-279. 

Antimicrobial agents as well as macrolide antibiotics and fluoroquinolones used in human and veterinary medicine are of particular interest due to their potential for... 

ERAVMIS Environmental Risk Assessment of Veterinary Medicines in Slurry, 1999-2003), whose aim was to evaluate the impact of some veterinary antibiotics (mainly macrolides and sulphonamides)... 

Spiramycin is another macrolide, recently introduced into medicine for the treatment of toxoplasmosis, infections caused by the protozoan Toxoplasma gondii. This contains a 16-membered lactone ring (erythromycin has a 14-membered ring), and two aminosugars, o-mycaminose and o-forosamine. o-Forosamine is remarkable in having only one hydroxyl group, and that is bound up in the hemiacetal ring system. 

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-... 

Tilmicosin is a macrolide antibiotic exclusively used in veterinary medicine and resembling tylosin. It is approved for treatment of respiratory diseases in beef cattle and sheep by the subcutaneous route (100, 101). It is also indicated for treatment and control of respiratory diseases associated with mycoplasma in broiler chickens, but not in laying hens. Of major significance is that in contrast to other macrolides, tilmicosin is not safe for use in swine since fatalities may occur at dosage as low as 20 mg/kg bw (7). 

The importance of fermentation-derived antibiotics in veterinary medicine continues to increase. The following two classes of antibiotics, the macrolides and glycosides, were all obtained as metabolites of various Streptomyces species. 

The avermectins (Figure 3.67) have no antibacterial activity, but possess anthelmintic, insecticidal, and acaricidal properties, and these are exploited in human and veterinary medicine. The avermectins are also 16-membered macrolides, but their structures are made up from a much longer... 

Erythromycin may cause increases in the semm levels of simvastatin. The CSM has advised that this should not be co-prescribed with simvastatin. In the first instance the pharmacist should check local policies for management of hospital acquired chest infections/pneumonia to ascertain first and second line choices. If erythromycin or any macrolide cannot be avoided then a practical way forward may be to avoid taking any dose of simvastatin for the duration of the course of macrolide. In addition a recent Dmg Safety Update from the Medicines and Healthcare Products Regulatory Agency (MHRA, 2008) on statins has highlighted statin dmg interactions and the appropriate actions to take. 

Pharmaceutical applications of metathesis are widespread in the patent literature. While CM and ROM are applicable in some syntheses, it is RCM which predominates, as there are few reactions which are as effective for synthesis of highly functionalized medium ring compounds. Such macrolides are key components of a vast range of medicinally active compounds which can combat bacterial and viral infections as well as cancers, bone and neurological... 

Bryostatins are medicinally important macrolides discovered from the cosmopohtan bryozoan Bugula neritina (2). Twenty bryostatins, which all possess a 20-membered ring, are known to date. Bryostatin 1 (33) showed good antitumor activity it selectively modulates protein kinase C (12). 

An important consideration in the agricultural production of plants containing medicinally active components is that they are sometimes produced by, or in consequence of, microbial agents present in or on the plant. These also constitute part of the biodiversity regulated by law, may be pathogenic to other economic crops and are not always easily cultured. Production in the natural habitat raises no problems. As an example one may notice that the maytansinoids, ansa-macrolides, which form part of the chemical make-up of Maytenus ilicifolia and M. aquifolia, Celastraceae, the two species most highly considered for stomach ulcer treatment, have been shown to be produced by bacteria associated with the plants. ... 

MC-352 or YM-17K), which had improved activity against Haemophilus influenzae [124-126]. However, despite many intensive efforts, a macrolide within the tylosin related family has not yet found a position in human medicine. 

Erythromycins, the representative and medicinally important macrolide antibiotics, have been widely studied and are still undoubtedly one of the most challenging target molecules for many synthetic organic chemists (O Fig. 3). Woodward and coworkers accomplished the first total synthesis of erythromycin A (18) in 1981 [8,9,10]. Corey and coworkers synthesized erythronolides A (20) and B (21), the aglycons of erythromycins A (18) and B (19), in 1978 [11,12] and 1979 [13]. 

It has been shown for avermectin B that the hydroxyl group at C-5 and a disaccharide moiety are essential for antiparasitic, mitocidal and selective insecticidal activities. Chemical modification of the macrolide-type avermectins resulted in ivermectin which was commercialized to be used in agriculture and animal health care as well as in human medicine. 

This class of macrolide antibiotic has mostly antiparasitic activity. Avermectin Bia (45) and ivermectin (46) (O Scheme 18) are used mostly in veterinary medicine, however, some semisynthetic derivatives are also used for treatment of onchocerciasis in humans [59]. The action of avermectin is believed to stimulate specific chloride ion transport systems increasing the membrane permeability to Cl ions via GABA (y-butyrate) receptors and non-GABA receptors [60]. 

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