[Effects of ristocetin, novobiocin, tetracycline-oleandomycin, oleandomycin, tetracycline, dihydrostreptomycin, penicillin and chloramphenicol on chick embryos].
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Anti-Bacterial Agents↗
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Combined antibiotic therapy of chronic amebic colitis with oxytetracycline-oleandomycin and tetracycline-oleandomycin.
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Amebiasis↗
In vitro study of the action of a tetracycline-oleandomycin preparation. Tetracycline, oleandomycin, and chloramphenicol on Staphylococcus, Escherichia coli, and Klebsiella.
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Anti-Bacterial Agents↗
Effect of tetracycline, oleandomycin, and a mixture of tetracycline and oleandomycin on staphylococci in vitro and in nasal carriers.
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Anti-Bacterial Agents↗
[Studies on the in vitro sensitivity of strains of Micrococcus pyogenes var. aureus to tetracycline, oleandomycin and mixtures of tetracycline and oleandomycin].
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Anti-Bacterial Agents↗
[Report on the clinical use of oleandomycin and of an oleandomycin-tetracycline combination in gynecology (with special reference to intravenous application)].
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Anti-Bacterial Agents↗
Resistance to oleandomycin in Streptomyces antibioticus, the producer organism.
Resistance to oleandomycin in Streptomyces antibioticus, the producer organism, was studied. The organism was highly resistant in vivo to the antibiotic but sensitive to other macrolides and lincosamides. Protein synthesis in vivo by mycelium of S. antibioticus was more resistant to oleandomycin than that by mycelium of Streptomyces albus G, an oleandomycin-sensitive strain, and this resistance was dependent on the age of the culture, older mycelium of S. antibioticus being more resistant to oleandomycin than young mycelium. [3H]Oleandomycin was capable of binding to the same extent to the 50S subunits of the ribosomes of both organisms. Oleandomycin also inhibited in vitro protein synthesis by ribosomes obtained from an oleandomycin-production medium at the time when maximum levels of oleandomycin were being produced. A clear difference between the ability of the two organisms to incorporate exogenous oleandomycin was observed. Thus, while S. albus G took up oleandomycin, S. antibioticus showed a decreased permeability to the antibiotic, suggesting a role for cell permeability in self-resistance.
Bacterial Proteins↗
A second ABC transporter is involved in oleandomycin resistance and its secretion by Streptomyces antibioticus.
A 3.2 kb Sstl-Sphl DNA fragment of Streptomyces antibioticus, an oleandomycin producer, conferring resistance to oleandomycin was sequenced and found to contain an open reading frame of 1710 bp (oleB). Its deduced gene product (OleB) showed a high degree of similarity with other proteins belonging to the ABC-transporter superfamily including the gene product of another oleandomycin-resistance gene (OleC). The OleB protein contains two ATP-binding domains, each of approximately 200 amino acids in length, and no hydrophobic transmembrane regions. Functional analysis of the oleB gene was carried out by deleting specific regions of the gene and assaying for oleandomycin resistance. These experiments showed that either the first or the second half of the gene containing only one ATP-binding domain was sufficient to confer resistance to oleandomycin. The gene oleB was expressed in Escherichia coli fused to a maltose-binding protein (MBP) using the pMal-c2 vector. The MBP-OleB hybrid protein was purified by affinity chromatography on an amylose resin and polyclonal antibodies were raised against the fusion protein. These were used to monitor the biosynthesis and physical location of OleB during growth. By Western analysis, the OleB protein was detected both in the soluble and in the membrane fraction and its synthesis paralleled oleandomycin biosynthesis. It was also shown that a Streptomyces albus strain, containing both a glycosyltransferase (OleD) able to inactivate oleandomycin and the OleB protein, was capable of glycosylating oleandomycin and secreting the inactive glycosylated molecule. It is proposed that OleB constitutes the secretion system by which oleandomycin or its inactive glycosylated form could be secreted by S. antibioticus.
ATP-Binding Cassette Transporters↗
Intracellular glycosylation and active efflux as mechanisms for resistance to oleandomycin in Streptomyces antibioticus, the producer organism.
Resistance to macrolides in producing organisms can be achieved by target site modification, intracellular inactivation of the antibiotic or active efflux mechanisms for the excretion of the antibiotic. The oleandomycin producer, Streptomyces antibioticus, possesses oleandomycin-sensitive ribosomes all along the cell cycle. However, it contains an intracellular glycosyltransferase capable of inactivating oleandomycin in the presence of UDP-glucose as cofactor. The correspondent gene (oleD) has been cloned and sequenced and the glycosyltransferase purified. Two other genes (oleB and oleC) that confer oleandomycin resistance have been cloned and characterized and both encode ABC (ATP-Binding Cassette) transporters. These may constitute the excretion mechanism throughout which the glycosylated oleandomycin is excreted. A second enzyme activity has been purified from culture supernatants of the oleandomycin producer that releases the glucose from the inactive glycosylated oleandomycin generating active antibiotic. This enzyme would probably catalyse the last step in the biosynthesis of oleandomycin.
Amino Acid Sequence↗
Identification and antibacterial activity of a new oleandomycin derivative from Streptomyces antibioticus.
During the study on the oleandomycin production, we purified a new oleandomycin derivative having a macrolactone of which biosynthesis does not follow the genetic architecture of the oleandomycin PKS. The molecular formula for the compound was suggested as C35H59NO11 on the basis of the analysis of NMR and HRMS data (m/z 670.4185, Delta-1.9mmu, calcd for C35H60NO11). 13C NMR assignments and analysis of COSY, HMBC and HMQC data suggested that the compound differs from oleandomycin by formation of the olefinic functionality resulting from the dehydration of a hydroxy group in oleandomycin. The new oleandomycin derivative has antibacterial activities similar to those of oleandomycin agaisnt Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus.
Anti-Bacterial Agents↗
Two glycosyltransferases and a glycosidase are involved in oleandomycin modification during its biosynthesis by Streptomyces antibioticus.
A 5.2 kb region from the oleandomycin gene cluster in Streptomyces antibioticus located between the oleandomycin polyketide synthase gene and sugar biosynthetic genes was cloned. Sequence analysis revealed the presence of three open reading frames (designated oleI, oleN2 and oleR). The oleI gene product resembled glycosyltransferases involved in macrolide inactivation including the oleD product, a previously described glycosyltransferase from S. antibioticus. The oleN2 gene product showed similarities with different aminotransferases involved in the biosynthesis of 6-deoxyhexoses. The oleR gene product was similar to several glucosidases from different origins. The oleI, oleR and oleD genes were expressed in Streptomyces lividans. OleI and OleD intracellular proteins were partially purified by affinity chromatography in an UDP-glucuronic acid agarose column and OleR was detected as a major band from the culture supernatant. OleI and OleD showed oleandomycin glycosylating activity but they differ in the pattern of substrate specificity: OleI being much more specific for oleandomycin. OleR showed glycosidase activity converting glycosylated oleandomycin into active oleandomycin. A model is proposed integrating these and previously reported results for intracellular inactivation, secretion and extracellular reactivation of oleandomycin.
Amino Acid Sequence↗
Analysis of a Streptomyces antibioticus chromosomal region involved in oleandomycin biosynthesis, which encodes two glycosyltransferases responsible for glycosylation of the macrolactone ring.
A 6-kb region from the chromosome of Streptomyces antibioticus, an oleandomycin producer, was cloned and sequenced. This region was located between the 3' end of the gene encoding the third subunit of the oleandomycin type I polyketide synthase and the oleP and oleB genes, which encode a cytochrome P450 monooxygenase and an oleandomycin resistance gene, respectively. Analysis of the nucleotide sequence revealed the presence of five genes encoding a cytochrome P450-like protein (oleP1), two glycosyltransferases (oleG1 and oleG2) involved in the transfer of the two 6-deoxysugars (L-oleandrose and D-desosamine) to the oleandomycin macrolactone ring, a methyltransferase (oleM1), and a gene (oleY) of unknown function. Insertional inactivation of this region by gene disruption generated an oleandomycin non-producing mutant which accumulated a compound that, according to mass spectrometry analysis, could correspond to the oleandomycin macrolactone ring (oleandolide), suggesting that the mutation affects oleandrosyl glycosyltransferase.
Amino Acid Sequence↗
Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives.
Chemical modification of the macrolide antibiotic oleandomycin (C-1) is described. Reductive amination of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (C-6) with ammonium acetate provides amino-oleandomycin derivative C-7 in which the 4"-amine is oriented in the axial configuration. The structure-activity relationship of a series of 4"-sulfonamide analogs prepared from amino-oleandomycin derivative C-7 is discussed. Noteworthy is the significant in vitro potency enhancement of the para-chlorobenzenesulfonamide analog C-12 over that of the parent oleandomycin. The absolute configuration of the 4"-amino-oleandomycin derivative C-7 was established through X-ray analysis of the para-iodobenzenesulfonamide analog C-14.
Animals↗
[The clinical effect of antibiotics in the macrolide family on bronchial asthma. Non-antimicrobial actions of oleandomycin [author's transl)].
Non-antimicrobial actions of oleandomycin (triacetyloleandomycin and oleandomycin phosphate) were studied in patients with bronchial asthma. Twenty-one cases of the disease without associating infections entered the study, and they were given 750mg of oleandomycin or triacetryloleandomycin in three divided doses daily for two weeks. Clinical manifestations and laboratory findings were compared to assess the effectiveness of the antibiotic therapy between the three 2-week periods before, during and after the therapy. Improvements in clinical manifestations were attained in 11 of 21 cases (52.3%), and last after discontinuance of the therapy in 8(38.1%). The blood level of 11-OHCS as determined by the Demoorr's fluorescence method increased by greater than 20% at the end of thearpy in 7 of 18 cases (38.9%). In 5 of the 7 cases favorable responses were seen clinically to the oleandomycin therapy. The serum IgE level determined by the radioimmunosorbent test was compared before and after the therapy to reveal that oleandomycin caused decrease of IgE in 10 and increase in 9 of 20 cases examined. The oleandomycin therapy resulted increases by greater than 20% of the vital capacity and FEV 1.0 in 2 and 3, respectively, of 15 cases. Jaundice in association with elevations of the GOT, GPT and alkaline phosphatase developed in one patient, and generalized skin eruption in another. Both of these cases were given triacetyloleandomycin.
11-Hydroxycorticosteroids↗
Cloning, characterization and heterologous expression of a polyketide synthase and P-450 oxidase involved in the biosynthesis of the antibiotic oleandomycin.
The gene cluster encoding the deoxyoleandolide polyketide synthase (OlePKS) was isolated from the oleandomycin producing strain Streptomnyces antibioticus. Sequencing of the first two genes encoding OlePKS, together with the previously identified third gene revealed an overall genetic and protein architecture similar to that of the erythromycin gene cluster encoding the 6-deoxyerythronolide B synthase (DEBS) from Saccharopolyspora erythraea. When the entire OlePKS (10,487 amino acids) was expressed in the heterologous host Streptomyces lividans, it produced 8,8a-deoxyoleandolide, an aglycone precursor of oleandomycin. The role of the P-450 monooxygenase, OleP, in oleandomycin biosynthesis was also examined in vivo by co-expression with DEBS in S. lividans. The production of 8,8a-dihydroxy-6-deoxyerythronolide B and other derivatives indicates that OleP is involved in the epoxidation pathway of oleandomycin biosynthesis. Since there are currently no genetic systems available for manipulation of the natural oleandomycin producing strain, the heterologous expression system reported here provides a useful tool for studying this important macrolide antibiotic.
Anti-Bacterial Agents↗
[Inhibition of oleandomycin biosynthesis by glucose].
The results of the study on the effect of glucose and various carbohydrates on biosynthesis of oleandomycin by Streptomyces antibioticus are presented. It was found that glucose added at the beginning or by the 48th hour of the fermentation process on the complex medium inhibited oleandomycin biosynthesis. To investigate the mechanism of the glucose effect, a fermentation medium was developed. It provided variation of the carbohydrate composition, determination of the protein content in the culture and evaluation of the mycelium productivity. With the use of this medium it was shown that monosaccharides such as galactose, fructose and glucose significantly activated the mycelium growth as compared to lactose and sucrose. At the same time glucose completely inhibited oleandomycin biosynthesis when added either as an only carbohydrate component or in combination with galactose or fructose, while the presence of the other two monosaccharides did not prevent antibiotic production, though the mycelium productivity was lowered as compared to that with the use of the disaccharide. Therefore, the inhibitory effect of glucose on biosynthesis of oleandomycin was not connected with activation of the culture growth by it. Acidification of the medium on cultivation of the streptomycete in the presence of glucose only partially explained its inhibitory effect, since inhibition was maintained on the medium with addition of CaCO3 which stabilizes pH. Addition of 2-deoxy-D-glucose, a nonmetabolized glucose analog, to the fermentation medium retarded antibiotic production. It is possible that the inhibitory effect of glucose on biosynthesis of oleandomycin is not associated with its metabolism.
Culture Media↗
The international standard for oleandomycin.
At the request of the WHO Expert Committee on Biological Standardization a batch of oleandomycin was submitted to an international collaborative study in six laboratories situated in four countries. In this study the material was assayed by plate diffusion methods, which varied in details of technique and design, against the US Food and Drug Administration's reference preparation for oleandomycin. On the basis of the results obtained the material has been established as the International Standard for Oleandomycin and the International Unit of Oleandomycin is defined as the activity in 0.001176 mg of the International Standard. The US Food and Drug Administration's standard and the International Standard are each part of the same parent batch of oleandomycin and the validity of such an assay has been compared with the more usual assay situation when there is some degree of difference between the preparations under comparison.
Biological Assay↗
[Polarographic method of determining oleandomycin].
It was shown with the use of classical and differential polarography that oleandomycin in aqueous solutions undergoes electrolytic reduction on the mercury-dropping electrode. The polarographic wave of the reduction was distorted with adsorption phenomena. Its height was proportional to the analytical concentration of oleandomycin in the solution. The polarographic study on the process of acid and alkaline hydrolysis showed a satisfactory correlation between the height of the oleandomycin peak on the differential polarogramme [Formula: see text] and the biological activity of the antibiotic in the solution. The quantitative analysis implies recording of the data of the differential polarogramme of the test-solution and measurement of the antibiotic concentration with the calibration graph. Comparison of the results of determination of the oleandomycin levels in oleandomycin phosphate drugs and fermentation broth filtrates with the polarographic and micro-biological methods revealed no systematic deviations and showed that the average casual deviation between the results was due only to the errors of the methods reproducibility.
Biological Assay↗