Macrolide antibiotics, biosynthesis producers

S. antibioticus produces another unusual macrolide antibiotic [45] called chlorothricin (57) containing, in addition to the aglycone (modified methylsalicylic acid), saccharides, dideoxyhexoses in the first place. Their biosynthesis was investigated by the incorporation of stable isotopes [45-47]. The compounds were only active in a synthetic medium and inactive in a complex one [48]. Compounds designated MC031-034 (58-61) are similar to chlorothricin mentioned above and were isolated from the cultivation broth of Streptomyces sp. collected in Japan. Another compound, 2-hydroxychlorothricin (62), with antitumor activity, was isolated [66] from Streptomyces K818. 

Omura S. Sadakane N, Tanaka Y, Marsiibara H. Chimeramycins New macrolide antibiotics produced by hybrid biosynthesis. J Antibiot 1983 36 927-930. 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Macrolides, lincosamides and streptogramins are protein biosynthesis inhibitors that bind to 50S subunit of the ribosome and inhibit peptidyl tRNA translocation from the A-site to the P-site." Macrolides have a glycosylated 14-, 15- or 16-membered lactone ring structure and are produced by several species of Streptomyces. Lincosamide antibiotics were isolated initially from Streptomyces lincolnensis but later isolated from different species of Streptomcyces. Streptogramins were also isolated from Streptomycesgraminofaciens and subsequently from several different Streptomyces species. There are two structurally different streptogramins, A and B they are bacteriostatic individually and can be bactericidal when combined. 

The biosynthesis of erythromycin can be divided into two phases (Scheme 1). In the first constructive phase of the pathway a set of key enzymes, collectively known as the polyketide synthase (PKS), assembles the typical polyketide chain by sequential condensation of one unit of propionyl-CoA and six units of methylmalonyl-CoA 6. The initially formed chain is cyclised to give the first macrocychc lactone (macrolide) intermediate 6-deoxyerythronolide B 7 [6,7]. In the second phase 6-deoxyerythronohde B is elaborated by a series of tailoring enzymes which carry out regiospecific hydroxylations, glycosylations and a methylation (of an added sugar residue) to give finally erythromycin A. The core polyketide structure is generated by the PKS in phase one, but the later steps of phase two are essential to produce active antibiotics. 

Tylosin [46-49] (Fig. 6), produced by Streptomyces fradiae, was one of the first antibiotics for which a comprehensive set of blocked mutants was isolated. They were used to help define the biosynthetic pathway. Whereas erythromycin is a 14-membered macrolide, tylosin has a 16-membered lactone structure. The gene for the final step of biosynthesis was cloned by reverse genetics from the protein sequence of the enzyme [46], and specific segments of surrounding DNA were found to complement other classes of blocked mutants. The formation of tylosin aglycon, protylonolide, is involved in five polyketide synthases. 

Mutant strains of macrolide-producing microorganisms, in which different steps of macrolide biosynthesis have been blocked, have yielded a wide variety of new compounds representing biosynthetic intermediates and shunt metabolites. This approach has been employed especially with Streptomyces fradiae, producer of the commercially important veterinary antibiotic tylosin three groups have independently isolated and identified many fermentation products which differ from tylosin in the number or type of saccharides and/or degree of... 

The structure of rimocidin (from S. rimosus), which contains mycosamine attached to a polyene macrolide ring, has been reported. 3-0-(2,6-Dideoxy-a-L-ribo- and -flm6mo-hexopyranosyl)erythronolide B, aberrant metabolites in the biosynthesis of erythromycin, have been isolated from the fermentation broth of S. erythreus, an erythromycin-producing organism. A new lankamycin antibiotic, isolated from the fermentation broth of S. violaceoniger, has been shown to contain the unsaturated derivative 4-0-acetyl-2,3,6-trideoxy-3-C-methyl-L-tAreo-hex-2-enopyranose (379) in place of 4-O-acetylarcanose (4-0-acetyl-2,6-dideoxy-3-C,0-dimethyl-L-xry/o-hexo3e). ... 

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