Antibiotic aminoglycoside

New antibiotics reported this year have included several groups of closely related pseudo disaccharides fortimicin C, a carbamoyl derivative of fortimicin A (1), fortimicin D, the 6 -demethylated analogue of fortimicin A, and fortimicin KE, the d -demethylated derivative of fortimicin B (2), have been isolated from the culture broth of Micromonospora olivoasterospora, which also yields fortimicin A and and sporaricin A (3, = NHjCHaCO-) and sporaricin B (3, = H) 

Istamycin A (4) and istamycin B (5) have been isolated from the culture broth of Streptomyces tenjimariensis, and sannamycin A (identical with istamycin A) and sannamycin B (6) from the culture broth of Streptomyces sannan-ensis- these are likewise 1,4-diamino-cyclitol ot-glycosides of 6-A -methyl-purpurosamine C. (The synthesis of this amino-sugar is mentioned in Chapter 8.) Derivatives of the amino-sugar and cyclitol constituents of fortimicin B have been prepared by benzyloxycarbonylation and alcoholysis of the antibiotic.  

The structure (7) has been proposed for the heteropentasaccharide, virido-pentaose B, isolated from the antibiotic sporoviridin, which also contains two other pentasaccharides. A tetrasaccharide and a trisaccharide (8) composed of quinovose and viosamine were obtained by partial methanolysis of the pentaose (7) by removal of the 2-deoxy sugar units, the latter being characterized as the 3-amino-sugar, D-acosamine.  

Recent advances in the synthesis of aminoglycoside antibiotics have been reviewed. Derivatized dihydrostreptomycin has been hydrolysed to give a chiral streptidine derivative (9), which could be condensed with a dihydrostrepto-biosaminyl chloride derivative to give a- and j3-glycosides, the a-form yielding dihydrostreptomycin again on deprotection.  

4 -Dideoxykanamycin B can be prepared on a large scale from kanamycin B by hydrogenation of the corresponding 3-ene derivative obtained by established procedures via the 3, 4-epoxide. 5-Epikanamycin B has been prepared using 

The aminoglycoside antibiotics and chemical transformations on them have been reviewed. 

Several components have been separated from the seldomycin complex elaborated by Streptomyces hofunensis. Seldomycin factors 1 and 2 were identified as 6-0-(2-amino-2 deoxy-a-D-xylopyranosyl)paromamine (494) and 4 -deoxynea-mine, respectively factor 3 as, probably, (495) (i.e. the 6 -amino-6 -deoxy analogue of factor 1) and factor 5, which is the most active of these antibiotics, as 6-0-(2,3-diamino-2,3-dideoxy-4-0-methyl-a-D-xylopyranosyl)-4 -deoxyneamine (496  

Matsushima, K. Kitaura, and Y. Mori, Bull. Chem. Soc. Japan, 1977, 50, 3039. 

Among other new aminoglycoside antibiotics were the pseudotrisaccharide-peptide derivative, -. 668 

Micromonospora inyoensis [the principal component of the complex is sisomicin (see Vol. 9, p. 134)] fortimicins A (499) and B (500), whidi are ycosides of 6-epi-purpurosamine B containing the novel aminocyclitol fortanaine (see also p. 147). N.m.r. spectroscopy showed that the iV-glycylfortamine unit of forti-midn A adopts the alternative chair conformation to that depicted in (499). Degradative and spectroscopic studies have established that ezomycins Bj, Bj, 

The aminoglycoside antibiotics constitute an important category of antibacterial agents in the therapeutic armamentarium, e.g., streptomycins, neomycins, paramomycins, kanamycins, gentamycins and the corresponding derivatives of these antibiotics. 

These are a bunch of closely related chemically basic carbohydrates that are mostly water-soluble. Their respective hydrochlorides and sulphates are crystalline in nature. They are found to be effective in inhibiting the growth of gram-positive as well as gram-negative bacteria. They are also effective to a great extent against mycobacteria. 

In general, they are prepared biosynthetically exclusively from an admixture of carbohydrate components of the fermentation media. 

They usually act by causing interference with the reading of the genetie eode. 

A few typical examples cited earlier shall be discussed below  

The biosynthesis of the aminoglycoside antibiotics has been reviewed. Apramycin, a broad-spectrum aminoglycoside antibiotic produced by a strain of Streptomyces tenebrarius, has been assigned the structure (361), which contains residues of 4-amino-4-deoxy-D-glucose and an octadiose that exists as a rigid bicyclic system. The structure (361), which was first derived from chemical and spectroscopic evidence, was confirmed by A -ray crystallographic analysis. 

Further reports on the structures of destomycin B (see Vol. 9, p. 131) and hikizimycin (see Vol. 9, p. 134) have appeared. The structure of minos-aminomycin (362), an aminoglycoside antibiotic obtained from a Streptomyces culture, has been established by degradation studies and partial synthesis. The aminoglycoside antibiotic G-52 produced by Micromonospora zionensis has been 

Shimura, Y. Sekizawa, K. linuma, H. Naganawa, and S. Kondo, Agric. and Biol. Chem. 

The carbohydrate components of actinridins A and B have been identified as D-mannose, L-actinosamine (3-amino-2,3,6-trideoxy-4-0-methyl-L-am6mo-hexo-pyranose), and 2-0-(3-amino-2,3,6-trideoxy-L-arc6mo-hexopyranosyl)-D-gluco-pyranose.  

Hydrolysis of flavumycin A, an aromatic heptaenic antibiotic, yielded mycos-amine (3-amino-3,6-dideoxy-D-mannose) and 4-acetylaniline.  

Reviews have appeared on the synthesis of aminoglycoside antibiotics, and on the formation of new aminocyclitol antibiotics by mutants of amino-cyclitol-producing organisms fed with aminocyclohexanol or related subunits. The structures of eight minor components of the nebramycin complex elaborated by Streptomyces tenebrarius have been elucidated besides neamine and related pseudo-disaccharides, the new components are pseudo-trisaccharides related to kanamycin B, and the 3 -hydroxy analogue of the principal component of the complex, apramycin (see Vol. 10, p. 130).  

A synthesis of the octodiose present in apramycin is referred to in Chapter 2. See also Chapter 14 for the synthesis of octadialdose derivatives. 

There have been many syntheses reported this year in quest of compounds with improved biological activity. Syntheses which involve glycosylation of streptamine derivatives have included the preparation of 4-0-(2-amino-2-deoxy-a-D-glucopyranosyl)- and 4-0-(6-amino-6-deoxy-a-D-glucopyranosyl)-2,5-dideoxystreptamine, the latter showing remarkable antimicrobial activity,  

5- deoxykanamycin A, which had only half the activity of kanamycin A, 3, 3 -dideoxy-butirosin A and 5 -amino-3, 5 -dideoxybutirosin A, both showing comparable activity to 3 -deoxybutirosin A, 6-0-(3-amino-3-deoxy-a- and )S-D-glucofuranosyl)-neamine, which are furanosyl isomers of kanamycin B,  

6- 0-(j8-D-ribofuranosyl) and 6-0-(a-D-arabinofuranosyl)-paromamine, which are less effective antibacterial agents than the corresponding amino-sugar 

The aminoglycosides act by inhibiting protein synthesis by interaction with the 30 ribosomal subunit. In the form used in therapeutics, namely, the salts of the amine with acid, the aminoglycoside antibiotics are cationic. 

Although many of the possible combinations have been used in clinical practice, the relative advantages and disadvantages of each combination have not been adequately elucidated. There is even considerable confusion about the in vivo or in vitro inactivation or synergy with the gen-tamicin/carbenicillin combination —a combination which has one of the longest records of clinical use in this series of combinations. Similarly, the relative nephrotoxicity of the various possible combinations is not clear.  

The papers given at a symposium on aminocyclitol antibiotics have been published most are reports of the synthesis of naturally occurring compounds or their conversion to modified analogues in search of improved antibiotic activity. A review has also appeared covering the structure, physicochemical and biological properties, structure-activity relationships, and mode of action of aminoglycoside antibiotics.  

A new antibiotic, S-ll-A, obtained from a mutant strain of Bacillus circulans, has been shown to be 1-deamino-1-hydroxy-xylostasin this contains a known biosynthetic precursor of the 2-deoxy-streptamine present in xylostasin.  

Degradation of the antibiotic sporaviridin has yielded two further pentasaccharides, viridopentaose A and C, which are closely related to viridopentaose B mentioned in last year s report (see Vol. 13, p. 158) viosamine is replaced by the corresponding simple sugars 6-deoxy-D-glucose and -D-glucose, respectively. N.m.r. evidence indicates that the acidic antitumour antibiotic neocarzinostatin contains 2,6-dideoxy-2-methylamino-galactose as a component of a chromo-phor attached to protein.  

Synthetic studies have shown that validamycin A has the structure and not the isomeric structure (8) previously proposed (see Vol. 6, p. 134). Glucosylation of validoxylamine A (7, R = R =H) by Rhodotorula lactosa gave a mixture of cl- and 3-D-glucosyl derivatives of these, the 4-j8-isomer was shown to be identical with validamycin A, the 4-a-isomer being validamycin D.  

Numerous reports describe the modification of natural amino-glycoside antibiotics or products derived from them by conventional methods. 1-/ -Alkylated kanamycins can be prepared very efficiently by utilizing an O N acyl migration to protect the sugar amino-groups selectively, leaving the deoxy-streptamine amino-groups free-, a formylation-deformylation sequence then 

Neamine analogues have been prepared in several studies in order to explore their potential as small molecule antitumour and anti-HIV agents, as well as bacterial enzyme inhibitors. 5-0-Alkylated neamines with polyamine functionality in the side-chain have been synthesized from 5-0-allylated precursors and these were found to exhibit high binding affinity for oncogene fusion proteins. The acylation of neamines at N-6 with aromatic units was carried out to explore the effect of these substituents on the interaction of neamine aminoglycosides with HIV RNA. Pyrene substituents were found to impart the most effective level 

Kanamycin A has also received some attention. Three analogues 207 each containing a 6-amino-6-deoxyglycofuranose moiety have been prepared by coupling with appropriate glycosyl chlorides and fluorides. All three compounds, however, were inactive in antibacterial screens.  

Reagents i, B0C2O, DMF, EtsN, H2O ii, triisopropylbenzenesulfonyl chloride, pyr iii, 2-aminoethanethiol, EtOH, EtONa iv, 9-phenoxyacridine, phenol v, 4M HQ, dioxane, 1,2-ethanedithiol 

4-N-glycyl and lysyl derivatives. The derivatives were found to 

2-unsaturated and 1,2-anhydro derivatives. 2-Deoxy-3-demethoxyfortimicin A has been synthesized from 1,2, 6 -tri-N-benzyloxycarbonyl-3-O-demethylfortimicin B, using the 

Tipson-Cohen procedure to prepare a 2,3-unsaturated intermediate from a 4,5-oxazolidine-2,3-dimesylate derivative. The in vitro antibiotic activity of this deoxy analogue was approximately twice that of fortimicin A. The conversion of fortimicin B to dactimicin (see Vol. 15, p.l76), which contains a N-2 formimino group, has been reported. N-Butyloxycarbonyl and benzyloxy-carbonyl groups were used to achieve selective formimidation of this 2 -amino group in the sequence -NHMe - N(Me)COCH2NH2 - N(Me)C0CH2NHCH = NH. A similar sequence has been used to convert istamycin Aq and Bq to the newly isolated component 

Synthesis of the 3-demethoxy-3-fluoro-sporaricin A analogues (12) from sporaricin B has been achieved using diethylaminosulphur trifluoride (DAST) as the fluorinating reagent on intermediate 3-hydroxyepimines. The difluoro analogue (13) was similarly 

2-deoxyfortimicin B, showing only very weak antibiotic 

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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. 

Aminoglycoside antibiotics and / -substituted indoles are stained red. Pyrrole derivatives with free / -positions react at room temperature to yield blue-colored zones [11]. Exposure to the vapors of aqua regia deepens the colors. This reaction sometimes produces fluorescence [3]. The detection limit for monomethylhydrazine is 200 pg per chromatogram zone [3]. 

Primary ( ) amines e.g. alkyl amines [1—3] lipid amines [4] a, co-diamines [5, 6] polyamines [6] alkanol amines [7] subst. anilines [8] aminoglycoside antibiotics [9, 10] biogenic amines [11] hydrazines... 

Enzymes transferring an acetyl moiety to one specific of several amino-groups of the aminocyclitol-aminoglycoside antibiotics (e.g. gentamicin, amikacin, kanamycin) are called aminoglycoside acetyltransferases... 

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

Smith CA, Baker EN (2002) Aminoglycoside antibiotic resistance by enzymatic deactivation. Curr Drug Targets Infect Disord 2 143-160... 

ATC JOlGBll JOIKD Use aminoglycoside antibiotic (against urinary and respiratory tract infections)... 

Amino-2, 5-dichlorobenzophenone (ADB) 226,227 4-Amino-2,3-dimethyl-l-phenyl-3-pyrazolin-5-one 158 2-Aminodiphenyl reagent 157,158 Aminoglycoside antibiotics 107, 270, 284, 354, 380, 423, 434... 

Aminoglycoside antibiotics la 107,270, 284,354,380,423,434 Amino groups lb 194 4-Aminohexoses, N-acetyl derivatives lb 233... 

The success of dibekacin prompted worldwide attention to the removal of selected OH groups in aminoglycoside antibiotics susceptible to modification by resistant bacteria, and the chemical deoxygenation procedure of D. H. R. Barton was found particularly useful. 

Further studies on the mechanism of resistance of aminoglycoside antibiotics focused on resistance genes existing in antibiotic-producer strains (mainly by Drs. Y. Okami and Kunimoto Hotta), and gradually clarified the relationship between the antibiotic-producing and -regulating mechanism. During this search, indolizomycin (1984) was discovered by cell fusion of two kinds of strains. 

Phosphorylative inactivation of aminoglycosidic antibiotics by Escherichia coli carrying R factor, H. Umezawa, M. Okanishi, S. Kondo, K. 

Biochemical mechanism of resistance to aminoglycosidic antibiotics, H. Umezawa, Adv. Carbohydr. Chem. Biochem., 30 (1974) 183-225. 

Simple analogs of an aminoglycoside antibiotic, 2,6-dideoxy-4-0- (671) and -5-0-(2,3-dideoxy-2-fluoro-o -D-r/Z>o-hexopyranosyl)streptamine (672) were prepared by coupling of tri-O-acetyl-2-fluoro-D-glucal (666) with cyclitol derivatives 668 or 667 (through 669 and 670) as shown. 

The prominent role played by Japanese investigators in carbohydrate science is underscored by the two substantial chapters by Japanese authors in the current volume. This volume also pays tribute to one of the greatest Japanese carbohydrate scientists, Hamao Umezawa, in the obituary article contributed by Tsuchiya, Maeda, and Horton. Hamao Umezawa dedicated his entire, extraordinarily productive career to the development of antibiotics his innovative contributions are exemplified by his chapter in Volume 30 of this series on the biochemical mechanism of inactivation of aminoglycoside antibiotics. 

Fig. 5.10 Some aminoglycoside antibiotics A, streptomycin B, kanamycins C, gentamicins D, amikacin.

Aminoglycoside antibiotics Reduced ability of cells to take up drugs... 

Fig. 25.6 Relationship between concentration of aminoglycoside antibiotic and the transfer of radioactivity from adenosine triphosphate to phosphocellulose.

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