New semisynthetic fluorinated "hybrid" macrolides.

Toscano, L.; Fioriello, Giuseppe; Spagnoli, Roberto; Cappelletti, Leonardo

doi:10.7164/antibiotics.36.1585

Cited by 4 publications

(2 citation statements)

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“…This resulted in the second generation of macrolides, which were semisynthetic derivatives of the first, natural product, generation. Five derivatives of erythromycin were developed and marketed, namely, clarithromycin (Omura et al ., ), dirithromycin (Counter et al ., ), roxithromycin (Chantot et al ., ), flurithromycin (Toscano et al ., ; Gialdroni‐Grassi et al ., ) and azithromycin (Girard et al ., ; Retsema et al ., ) (Figure ). Miokamycin (Omoto et al ., ; Borzani et al ., ) and rokitamycin (Sakakibara et al ., ) were the only 16‐membered second‐generation compounds developed for human use (Figure ).…”

Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 98%

“…Five derivatives of erythromycin were developed and marketed, namely, clarithromycin (Omura et al, 1992), dirithromycin (Counter et al, 1991), roxithromycin (Chantot et al, 1986), flurithromycin (Toscano et al, 1983;Gialdroni-Grassi et al, 1986) and azithromycin Retsema et al, 1987) (Figure 1). Miokamycin (Omoto et al, 1976;Borzani et al, 1989) and rokitamycin (Sakakibara et al, 1981) were the only 16-membered second-generation compounds developed for human use (Figure 2).…”

Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 99%

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The macrolide antibiotic renaissance

Dinos

2017

British J Pharmacology

327

221

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Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.

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Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 98%

Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 99%

The macrolide antibiotic renaissance

Dinos

2017

British J Pharmacology

327

221

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Macrolides

Kirst¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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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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Structural Modification of Macrolide Antibiotics

Kirst

1990

Recent Progress in the Chemical Synthesis of Antibiotics

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New semisynthetic fluorinated "hybrid" macrolides.

Cited by 4 publications

References 8 publications

The macrolide antibiotic renaissance

The macrolide antibiotic renaissance

Macrolides

Structural Modification of Macrolide Antibiotics

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