-
Nature Synthesis Jul 2022Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs...
Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, owning to their diverse and complex architecture, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semi-synthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a Cu-catalyzed, enantioselective, dearomative hydroamination, which set the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds.
PubMed: 36213185
DOI: 10.1038/s44160-022-00080-x -
Applied Biochemistry and Biotechnology Feb 2011Ribostamycin is a 4,5-disubstituted 2-deoxystreptamine (DOS)-containing aminoglycoside antibiotics and naturally produced by Streptomyces ribosidificus ATCC 21294. It is...
Ribostamycin is a 4,5-disubstituted 2-deoxystreptamine (DOS)-containing aminoglycoside antibiotics and naturally produced by Streptomyces ribosidificus ATCC 21294. It is also an intermediate in the biosynthesis of butirosin and neomycin. In the biosynthesis of ribostamycin, DOS is glycosylated to generate paromamine which is converted to neamine by successive dehydrogenation followed by amination, and finally ribosylation of neamine gives ribostamycin. Here, we report the biosynthesis of 6'-deamino-6'-hydroxyribostamycin (a ribostamycin derivative or pseudoribostamycin) in Streptomyces venezuelae YJ003 by reconstructing gene cassettes for direct ribosylation of paromamine. A trace amount of pseudoribostamycin was detected with ribostamycin in the isolates of ribostamycin cosmid heterologously expressed in Streptomyces lividans TK24. It has also indicated that the ribosyltransferase can accept both neamine and paromamine. Thus, the present in vivo modification of ribostamycin could be useful for the production of hybrid compounds to defend against bacterial resistance to aminoglycosides.
Topics: Biosynthetic Pathways; Gene Expression; Genes, Bacterial; Genetic Techniques; Multigene Family; Ribostamycin; Spectrometry, Mass, Electrospray Ionization; Streptomyces
PubMed: 20676801
DOI: 10.1007/s12010-010-9045-6 -
Allergy Oct 2004
Topics: Adult; Anaphylaxis; Anti-Bacterial Agents; Drug Hypersensitivity; Female; Humans; Pelvic Inflammatory Disease; Recurrence; Ribostamycin
PubMed: 15355481
DOI: 10.1111/j.1398-9995.2004.00683.x -
Clinical Pharmacokinetics Feb 1992In the present study, ribostamycin concentrations in serum were measured by microbiological assay in 20 paediatric patients aged 3 months to 11 years after intramuscular...
In the present study, ribostamycin concentrations in serum were measured by microbiological assay in 20 paediatric patients aged 3 months to 11 years after intramuscular ribostamycin 10, 15 and 20 mg/kg. All pharmacokinetic parameters and statistical analyses were calculated by computer. These results showed that the absorption rate constant (ka), elimination rate constant (ke), time to peak serum concentration (tmax), elimination half-life (t1/2), apparent volume of distribution (Vd/F), total body clearance (CL) and area under the serum concentration-time curve (AUC) were significantly different in infants under 6 months from those in children over 3 years (p less than 0.05), except for the peak serum concentration (Cmax) and lag time from administration to the first appearance of drug in the serum (tlag) [p greater than 0.05]. The absorption of ribostamycin in infants was more rapid than that in children, but elimination was slower (p less than 0.05). The Vd/F and CL in infants were also larger than in children (p less than 0.01). There were significant positive correlations between Cmax, AUC and ribostamycin dosage (p less than 0.01). Pharmacokinetic parameters for infants and children were compared with those observed in adults, and it was found that ribostamycin absorption and elimination were more rapid in the paediatric patients. The Cmax in children and infants after intramuscular ribostamycin 10 mg/kg approached that in adults after an intramuscular dose of ribostamycin 500mg. Using a 1-compartment open pharmacokinetic model, the optimum intramuscular ribostamycin administration interval was estimated as 6.01 and 7.56h for children and infants, respectively, while the value was 8.5h in adults. When the drug was administered in multiple doses of 15 mg/kg intramuscularly every 8h, no accumulation occurred in children. It is suggested that ribostamycin be administered in intramuscular doses of 10 to 15 mg/kg twice daily in infants and 3 times daily in children, respectively.
Topics: Absorption; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Infant; Injections, Intramuscular; Male; Ribostamycin
PubMed: 1551291
DOI: 10.2165/00003088-199222020-00005 -
The Journal of Antibiotics Sep 1977A mutant of a neomycin-producting Streptomyces fradiae was found which synthesizes ribostamycin instead of neomycin. After a reverse mutation new colonies were obtained...
A mutant of a neomycin-producting Streptomyces fradiae was found which synthesizes ribostamycin instead of neomycin. After a reverse mutation new colonies were obtained producting neomycin again. Ribostamycin might thus be considered as an intermediate in the biosynthesis of neomycin.
Topics: Anti-Bacterial Agents; Bacteria; Fermentation; Mutation; Neomycin; Ribostamycin; Streptomyces
PubMed: 924894
DOI: 10.7164/antibiotics.30.720 -
The Journal of Antibiotics Oct 1978By the use of our improved colony selection technique, xylostasin and ribostamycin producing mutants were isolated from nitrosoguanidine treated Bacillus circulans B15M,...
By the use of our improved colony selection technique, xylostasin and ribostamycin producing mutants were isolated from nitrosoguanidine treated Bacillus circulans B15M, a producer of butirosins A and B. Among these structurally related aminoglycosides, ribostamycin is the well-known product of a Steptomyces and has not been isolated as a bacterial metabolite. A selected mutant of strain 306, which produces xylostasin and ribostamycin, was futher mutagenized in expectation of getting an improved strain having the ability to accumulate a large amount of ribostamycin in the culture broth. One mutant, strain 451, derived from strain 306, produced ribostamycin free of xylostasin.
Topics: Anti-Bacterial Agents; Bacillus; Bacteria; Butirosin Sulfate; Chromatography, Thin Layer; Fermentation; Microbial Sensitivity Tests; Mutation; Ribostamycin
PubMed: 81827
DOI: 10.7164/antibiotics.31.966 -
Biochemical and Biophysical Research... Dec 2001In the process of screening of proteins binding to ribostamycin in bovine liver using the affinity column chromatography, we found that ribostamycin inhibited the...
In the process of screening of proteins binding to ribostamycin in bovine liver using the affinity column chromatography, we found that ribostamycin inhibited the chaperone activity of protein disulfide isomerase (PDI), but it did not inhibit the isomerase activity. PDI was identified by SDS-PAGE, Western blotting, and N-terminal amino acid sequence analysis. A 100:1 molar ratio of ribostamycin to PDI was almost sufficient to completely inhibit the chaperone activity of PDI. The binding affinity of ribostamycin to purified bovine PDI was determined by the Biacore system, which gave a K(D) value of 3.19 x 10(-4) M. This suggests that ribostamycin binds to region distinct from the CGHC motif of PDI. This is the first report to describe the inhibitor of the chaperone activity of PDI.
Topics: Animals; Anti-Bacterial Agents; Binding Sites; Cattle; Enzymes, Immobilized; In Vitro Techniques; Kinetics; Liver; Molecular Chaperones; Protein Binding; Protein Disulfide-Isomerases; Ribostamycin
PubMed: 11741285
DOI: 10.1006/bbrc.2001.6105 -
Frontiers in Microbiology 2020The emergence of infections caused by bacterial pathogens that are resistant to current antibiotic therapy is a critical healthcare challenge. Aminoglycosides are...
Exploration of Antibiotic Activity of Aminoglycosides, in Particular Ribostamycin Alone and in Combination With Ethylenediaminetetraacetic Acid Against Pathogenic Bacteria.
The emergence of infections caused by bacterial pathogens that are resistant to current antibiotic therapy is a critical healthcare challenge. Aminoglycosides are natural antibiotics with broad spectrum of activity; however, their clinical use is limited due to considerable nephrotoxicity. Moreover, drug-resistant bacteria that cause infections in human as well as livestock are less responsive to conventional antibiotics. Herein, we report the antibacterial evaluation of five different aminoglycosides, including ribostamycin, against a panel of Gram-positive and Gram-negative pathogens. Eight of the tested bacterial strains are linked to gastrointestinal (GI) infections. The minimum inhibitory concentration (MIC) of ribostamycin against three different strains is in the range of 0.9-7.2 μM and against a strain of is 0.5 μM. We also found that the MIC of ribostamycin was considerably enhanced from 57.2 to 7.2 μM, an 8-fold improvement, when bacteria were treated with a combination of ribostamycin and ethylenediaminetetraacetic acid (EDTA). These findings demonstrate a promising approach to enhance the clinical potential of ribostamycin and provide a rational for its antibiotic reclassification from special level to non-restricted level.
PubMed: 32849365
DOI: 10.3389/fmicb.2020.01718 -
Drugs Under Experimental and Clinical... 1989The nephrotoxicity of ribostamycin and gentamicin was compared by urinalysis using 18 parameters. When a dose of 40 mg/kg per day was administered intramuscularly to... (Comparative Study)
Comparative Study
The nephrotoxicity of ribostamycin and gentamicin was compared by urinalysis using 18 parameters. When a dose of 40 mg/kg per day was administered intramuscularly to Fischer rats for 14 days, ribostamycin caused little change of parameters in urine volume, urine osmolality, urine protein, maltase and beta 2-microglobulin. A slight increase with ribostamycin was observed in alpha-fucosidase, beta-N-acetylglucosaminidase, leucine aminopeptidase, lactic dehydrogenase (LDH) and potassium, and a moderate increase was observed in acid phosphatase and alkaline phosphatase. On the other hand, gentamicin caused a large alteration in most parameters. Both antibiotics caused a change of the isoenzyme pattern of LDH1-5, but the pattern with ribostamycin was much closer to the normal pattern than with gentamicin. When a dose of 80 mg/kg of ribostamycin was compared with 10 mg/kg of gentamicin, alteration of urinary parameters was almost comparable. Histopathological observations of the kidney specimens of rats given 40 mg/kg per day showed no histological damage with ribostamycin except for a slight increase and enlargement of lysosomes of the proximal epithelial cells. However, significant histological damage was observed with gentamicin, consistent with the results obtained from urinalysis. Renal accumulation of ribostamycin at a single dose of 20 mg/kg was three times less than that of gentamicin. Ribostamycin caused slightly less nephrotoxicity in rats than kanamycin and far less than dibekacin at an equal dosage of 40 mg/kg per day for 14 days.
Topics: Animals; Anti-Bacterial Agents; Enzymes; Gentamicins; Kidney; Kidney Cortex; Kidney Diseases; Kidney Medulla; Male; Polyuria; Proteinuria; Rats; Ribostamycin; Urine
PubMed: 2591299
DOI: No ID Found -
The Journal of Antibiotics Nov 2009
Topics: Anti-Bacterial Agents; Framycetin; Magnetic Resonance Spectroscopy; Ribostamycin
PubMed: 19713992
DOI: 10.1038/ja.2009.88