Macrolide antibiotics, 16-membered toxicity

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]. 

FK506 (tacrolimus), a natural product of Streptomyces tukubaensis, is a 23-membered macrolide antibiotic that contains a unique hemiketal-masked, a,P-diketo amide moiety (Fig. 1) [1]. It has a mode of action and toxicity profile similar to those of cyclosporin A (CsA), an immunosuppressive cyclic undecapeptide produced by Tolypocladium inflatum (Fig. 1), which has been used clinically for two decades to prevent rejection on transplantation of organs, such as kidney, heart, liver, and bone marrow. The use of CsA has led to a remarkable increase of survival of all organ allografts and has fueled a dramatic increase in the number of kidney, liver, cardiac, and bone marrow transplants [2]. Thus, CsA has revolutionized transplantation surgery, both in terms of efficiency and quality of life of the patient. FK506 is said to be a more potent immunosuppressant than CsA and was approved for the treatment and prevention of kidney transplant rejection. 

Erythromycin A, the major fermentation component of S. erythraea, is a 14-membered ring macrolide that is used by medicinal chemists as the foundation for building semisynthetic derivatives of erythromycin antibiotics. (Macrohdes inhibit bacteria by interfering with microbial protein biosynthesis.) Semisynthetic macrolides are popular with clinicians because they can be administered orally and have relatively low toxicity. They are often used to treat respiratory tract infections, and have been especially effective against conditions such as Legionnaires disease and community-acquired pneumonia. Erythromycin therapy is often prescribed for individuals allergic to penicillin. One of the most widely used macrohde antibiotics... 

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