Semisynthetic macrolide antibacterials derived from tylosin. Synthesis of 3-O-acetyl-23-O-demycinosyl-4″-O-isovaleryltylosin and related compounds, as well as the 12,13-epoxy derivatives

Fishman, A. G.; Mallams, Alan K.; Rossman, Randall

doi:10.1039/p19890000787

Macrolides

Kirst¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

0

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Macrolide antibiotics are well‐established antimicrobial agents in both clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12‐, 14‐, or 16‐membered. Naturally occurring 14‐membered macrolides include erythromycin A (C 37 H 67 NO 13 ), erythromycin B (C 37 H 67 NO 12 ), erythromycin C (C 36 H 65 NO 13 ), erythromycin D (C 36 H 65 NO 12 ), erythromycin F (C 37 H 67 NO 14 ), and erythromycin E (C 37 H 65 NO 14 ), as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; some of the derivatives of erythromycin and oleandomycin include 2′‐ O ‐acetylerythromycin (C 39 H 69 NO 14 ), 2′‐ O ‐propionylerythromycin (C 40 H 71 NO 14 ), erythromycin ethyl carbonate (C 40 H 71 NO 15 ), and others. 16‐Membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include leucomycin A 1 (C 40 H 67 NO 14 ), leucomycin A 5 (C 39 H 65 NO 14 ), leucomycin A 7 (C 38 H 63 NO 14 ), midecamycin A 2 (C 42 H 69 NO 15 ), and others. A second large group of 16‐membered macrolides differs from the leucomycins in the substitution pattern of the aglycone. One difference is a methyl or hydroxymethyl group at C‐14. The most prominent member of this group is tylosin, an important veterinary antibiotic produced by S. fradiae. Tylosin and related products include tylosin (C 46 H 77 NO 17 ), relomycin (20‐dihydrotylosin) (C 46 H 79 NO 17 ), macrocin (C 45 H 75 NO 17 ), O ‐demethylmacrocin (C 44 H 73 NO 17 ), and others. Other macrolides have been made by chemical, bioconversion, or genetic manipulations which represent hybrids of structures within the 14‐membered family, within the 16‐membered family, or between the two families. The advent of molecular biology has opened new possibilities for producing hybrid macrolides. Genetic manipulations of biosynthetic pathways in macrolide‐producing microorganisms complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis (formerly Branhamella ), and Haemophilus ducreyi. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolides are obtained by controlled submerged aerobic fermentations of soil microorganisms. Although species of Streptomyces have dominated, species of Saccharopolyspora, Micromonospora, and Streptoverticillium are also well represented. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. Relatively few macrolides are used in veterinary medicine. The most important is tylosin (Tylan, Elanco Products), which is used to control chronic respiratory disease caused by Mycoplasma gallisepticum in poultry.

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Antibiotics, Macrolides

Kirst

¹

2001

Kirk-Othmer Encyclopedia of Chemical Technology

1

0

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Macrolide antibiotics are well‐established antimicrobial agents in clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be a 12‐, 14‐, or 16‐membered ring. Naturally occurring 14‐membered macrolides include erythromycin A and erythromycin B, as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; its semisynthetic derivatives include erythromycin ethyl succinate, roxithromycin, clarithromycin, azithromycin, dirithromycin, and others. More recently, the ketolide family has been discovered that exhibits activity against certain macrolide‐resistant strains, from which telithromycin and ABT‐773 are in clinical trials. The 16‐membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include josamycin (leucomycin A 3 ), spiramycin, and others. The most prominent member of the second group is tylosin, an important veterinary antibiotic. Semisynthetic 16‐membered macrolides include miokamycin, rokitamycin, AIV‐tylosin, and tilmicosin. The advent of molecular biology has opened new possibilities for producing novel macrolides by genetic manipulations of biosynthetic pathways from macrolide‐producing microorganisms (combinatorial biosynthesis) that complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus ; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis , Campylobacter sp., Chlamydia sp., and Helicobacter pylori . Some derivatives have shown promising activity against non‐tuberculous mycobacteria. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. A few macrolides are used in veterinary medicine, such as tylosin and tilmicosin which are used to control respiratory diseases and other infections in poultry, pigs, and cattle.

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