Aminoglycosides and Aminocyclitols

Aminoglycosides and aminocyclitols are antibiotics elaborated by bacteria of the genus Streptomyces and Micromonospora (1). Streptomycin, kanamycin, ami- 

Aminocyclitols are closely related to aminoglycosides. They differ in that aminoglycosides contain amino sugars joined by a glycosidic link, while aminocyclitols have the amino group on the cyclitol ring (3). The two major aminocyclitols are spectinomycin and apramycin. 

Most aminoglycosides are complexes of several almost identical components differing either in the degree of methylation of one amino sugar unit, as in the case of gentamicin, or in the stereochemistry of the disaccharide unit, as in the case of neomycin. Differences in the substitutions on the basic ring structures between the various aminoglycosides account for the relatively minor differences in antimicrobial spectra, patterns of resistance, and toxicity. 

The aminoglycosides interfere with bacterial protein synthesis by binding irreversibly to ribosome and could cause cell membrane damage. They may be inactivated by bacterial resistant enzymes but bacteria could also display resistance through ribosomal modifications or by decreased uptake of antibiotic into the bacterial cell. 

Apramycin is a broad-spectrum aminocyclitol antibiotic and component of the nebramycin complex, produced by a strain of Streptomyces tenebrarius. Use of this antibiotic is specifically aimed at mass therapy of colibacillosis and salmonellosis in veal calves and swine. It is administered to calves by intramuscular or oral route at a dose of 20-40 mg/kg body weight/day for 5 days, and to swine via the drinking water at a dosage of 7.5-12.5 mg/kg bw/day for 7 days, or via the feed at a rate of 100 mg/kg feed for 28 days. It is further used for treatment of colibacillosis in lambs given orally at a dosage of 10 mg/kg bw/day for 3-5 days, and for treatment of E. coli septicemia in poultry administered in the drinking water at a concentration of 250-500 mg/L for 7 days. In contrast to other aminoglycosides, apramycin is not used in human medicine. 

The aldehyde 4 can be prepared from neomycin B, and this has been used in a combinatorial synthesis of neomycin B mimetics 5 (R = Bu or CH2C02Me, R = side-chains of 12 different aminoacids), using Ugi-type four-component conden- 

Carbohydrate Chemistry, Volume 30 The Royal Society of Chemistry, 1998 

A new semisynthetic antibiotic, 89-07, has been prepared by V-ethylation of N-1 of the deoxystreptamine unit in gentamycin Cia- A study of the reaction of gentamycin with hydrated electrons, using pulse radiolysis, has been described.  

A cell-free extract of an acarbose-producing Actinoplanes sp. phosphorylates acarbose at 0-7 (i.e. the primary hydroxyl of the aminocyclitol unit). Some other papers of relevance to the chemistry of acarbose-like compounds are mentioned in Chapter 18. 

The new antitumour antibiotic pyrrolosporin A (11) is a macrolide with an unusual spiro-a-acyl tetronic acid moiety. It also contains a 4-amino-2,4,6-trideoxy-P-D-aru6mo-hexopyranose unit, a sugar not previously found in nature (see Vol. 24, p. 148-9 for the synthesis of this sugar in studies of antibiotic analogues), and methanolysis of pyrrolosporin A gave the methyl a-pyranoside, with the pyrrole unit still linked to the sugar. 

An extensive report from Prinzbach s laboratory has described the synthesis of the pseudodisaccharide sannamycin (1), its 2-epimer and various other isomers, including the enantiomers of sannamycin and its 2-epimer. A detailed study was made of the glycosylations necessary to assemble these sytems. Various other novel pseudodisaccharides have also been prepared, including the a-D-arabino-furanosyl systems 2 (R=H, a-NHa, jJ-NHa), and the pyranose these workers also describe a Ferrier carbocyclization at the disaccharide level, using an acid labile 2 -deoxy-disaccharide, to give the aminocyclitol derivative 4.  

Various aminoacyl and dipeptidyl derivatives of kanamycin A and metilmycin have been prepared by regioselective acylation of Cu(II) complexes. In an approach to overcoming resistance to aminoglycoside antibiotics, thought to be 

Streptomycin A and neomycin B have found novel use as effective displacer compounds in the ion-exchange displacement chromatographic separation of proteins. A paper on the H-nmr assignments of the kanamycins and butirosin A is mentioned in Chapter 21. 

There has been further work on aminocyclopentitol antibiotics. A series of eight analogues of trehazolin (11) has been prepared in which the a-D-glucopyr-anose unit is replaced by other mono- and disaccharides and by carbosugar 

Absorption extent from the gastrointestinal tract (GIT) is very low (of the order of 1-2% of administered dose), although higher bioavailability may be achieved in neonatal animals and where there is dismption of the intestinal mucosa, caused by, for example, parvovirus infection. Within the GIT, aminoglycosides are stable and excreted unchanged in feces. 

When AMDs are administered parenterally as aqueous solutions (usually intramuscularly), absorption into the 

PHARMACOKINETICS, DISTRIBUTION, BIOAVAILABILITY, AND RELATIONSHIP TO ANTIBIOTIC RESIDUES 

TABLE 2.2 Influence of Lipid Solubility of Antimicrobial Drugs on Pharmacokinetic Properties (ADME)  

Penetrate cell membranes poorly or not at all limited or no significant absorption from GIT except for acid-stable aminopeni-cillins, which have moderate but species-variable absorption distribution limited mainly to extracellular fluids concentrations in intracellular fluid, CSF, miUc, and ocular fluids low, but effective concentrations may be reached in synovial, peritoneal, and pleural fluids some penicillins actively transported out of CSF into plasma generally excreted, usually in urine, in high concentrations as the parent molecule some drugs actively secreted into urine and/or bUe biotransformation (e.g., in the liver) usually slight or absent 

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Fig. 3.1 Chemical structures of commonly used aminoglycosides and aminocyclitols.

Table 29.1 Physicochemical Methods for Aminoglycoside and Aminocyclitol Antibacterials in Edible Animal Products... 

Polymixins are strong bases, while aminoglycosides and aminocyclitols are weak bases, but polar and poorly lipid-soluble because of the presence of sugar residues in the molecules. 

Aminoglycoside and Aminocyclitol Antibiotics Reviews have appeared on new semi-synthetic aminoglycoside antibiotics, with particular reference to habekacin and polydeoxy-... 

A variety of bacterial genera have been shown to produce aminoglycoside-aminocyclitol antibiotics. These include Streptomyces, Micromonospora, Bacillus, and so on. Only those compounds emanating from Streptomyces are named -mycins (e.g., tobramycin) while others are -micins (gentamicin), -osins, -asins, or -acins. The biosynthetic pathways for the aminoglycosides and the control of their expression are not well-studied. Streptomycin is the exception. 

Aminocyclitols - This category of antibiotics includes both aminoglycosides and other antibiotics which contain aminocyclitol moieties but no aminosugar. Control or alteration of resistance development and the moderation of toxic effects are the major areas of research interest. A number of newer aminocyclitols, such as amikacin, sisomicin, verdamicin, netilmicin, were undergoing clinical examination, while tobramycin and amikacin became available for medical use.5,6... 

To date, cyanobacteria have rarely been reported to produce exclusively sugar-based secondary metabolites, such as the aminoglycosides or aminocyclitols typical of the actinomycetes. Flowever, it should be noted that part of the reason for their underrepresentation may be the fact that many natural products chemists do not focus on water-soluble metabolites, and thus standard extraction and isolation protocols strongly select against the isolation of polar, sugar-based compounds. 

In spite of the broad antibacterial spectrum of aminoglycosides and their effective utilisation in cases of severe bacterial diseases, world-wide attempts have been made to develop new aminoglycosides with improved properties and reduced side effects. A main goal in the development of new semi-synthetic products has been the selective protection and modification or elimination of the numerous hydroxyl-and amino groups, the exchange of specific aminosugars or aminocyclitols and the introduction of amino acids as in butirosin. 

Chiral cyclohexanones obtained by the Ferrier carbocyclization reaction are useful precursors for the synthesis of cyclitols and aminocyclitols, some of which are found in clinically important aminoglycoside antibiotics. Additionally, highly substituted cyclohexenones, prepared by the Ferrier carbocyclization followed by (3-elimination, can undergo various further transformations, also making these compounds potential chiral building blocks for the preparation of structurally complex compounds having cyclohexane unit(s). This section provides an overview of the reported synthetic strategies toward various types of natural products based on utilization of the Ferrier carbocyclization reaction. 

Bakkei EP. Aminoglycoside and aminocyciicol antibiotics Hygicnnycin B is an atypical bactericidal compound that exerts effects on celb of Escheridita colt characteristic for bacteriostatic aminocyclitols. J Gen Microbiol 1992 138 563—569. 

Aminoglycosides. Antibiotics ia the amiaoglycoside group characteristically contain amino sugars and deoxystreptamiae or streptamiae. This family of antibiotics has frequentiy been referred to as aminocyclitol amiaoglycosides. Representative members are streptomycia, neomycin, kanamycia, gentamicin, tobramycia, and amikacin. These antibiotics all inhibit proteia biosynthesis. 

Beside AAC enzymes two different enzyme classes, nucleotidyltransferases (ANT enzymes), and phosphotransferases (APH enzymes) modify the hydroxyl groups of aminocyclitol-aminoglycoside antibiotics. 

Other medicinally useful aminoglycoside antibiotics are based on the aminocyclitol 2-deoxystrepta-mine, e.g. gentamicin Ci from Micromonospora purpurea. Although streptamine and 2-deoxystrepta-mine are actually cyclohexane derivatives, they are both of carbohydrate origin and derived naturally from glucose. 

Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds. 

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