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PubMed2000

Formation of functional heterologous complexes using subunits from the picromycin, erythromycin and oleandomycin polyketide synthases.

BACKGROUND: Recently developed tools for the genetic manipulation of modular polyketide synthases (PKSs) have advanced the development of combinatorial biosynthesis technologies for drug discovery. Although many of the current techniques involve engineering individual domains or modules of the PKS, few experiments have addressed the ability to combine entire protein subunits from different modular PKSs to create hybrid polyketide pathways. We investigated this possibility by in vivo assembly of heterologous PKS complexes using natural and altered subunits from related macrolide PKSs. RESULTS: The pikAI and pikAII genes encoding subunits 1 and 2 (modules 1-4) of the picromycin PKS (PikPKS) and the eryAIII gene encoding subunit 3 (modules 5-6) of the 6-deoxyerythronolide B synthase (DEBS) were cloned in two compatible Streptomyces expression vectors. A strain of Streptomyces lividans co-transformed with the two vectors produced the hybrid macrolactone 3-hydroxynarbonolide. Co-expression of the same pik genes with the gene for subunit 3 of the oleandomycin PKS (OlePKS) was also successful. A series of hybrid polyketide pathways was then constructed by combining PikPKS subunits 1 and 2 with modified DEBS3 subunits containing engineered domains in modules 5 or 6. We also report the effect of junction location in a set of DEBS-PikPKS fusions. CONCLUSIONS: We show that natural as well as engineered protein subunits from heterologous modular PKSs can be functionally assembled to create hybrid polyketide pathways. This work represents a new strategy that complements earlier domain engineering approaches for combinatorial biosynthesis in which complete modules or PKS protein subunits, in addition to individual enzymatic domains, are used as building blocks for PKS engineering.

Anti-Bacterial Agents↗
PubMed2002

Pharmacokinetics of oleandomycin in dogs after intravenous or oral administration alone and after pretreatment with metamizole or dexamethasone.

The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of OLD alone (10 mg/kg as bolus), the elimination half-life (t 1/2 beta, volume of distribution (Vd,area), body clearance (ClB) and area under the concentration time curve (AUC) were 1.60 h, 1.11 L/kg. 7.36 (ml/kg)/min and 21.66 microg h/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of OLD alone, the t 1/2 beta, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean absorption time (MAT) and absolute bioavailability (Fabs) were 1.6 h, 5.34 microg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for Cmax (2.93 microg/ml) but the MAT value (2.23 h) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 microg/ml) and the tmax (0.5 h) and MAT (0.45 h) were lower.

Administration, Oral↗
PubMed2002

Analysis of erythromycin and oleandomycin residues in food by high-performance liquid chromatography with fluorometric detection.

A reliable and sensitive procedure is presented for the analysis of erythromycin (ERY) and oleandomycin (OLE) in food of animal origin, such as meat, liver, kidney, raw milk and egg. The method is based on a solid-phase extraction clean-up with a cation exchange cartridge, a 9-fluoromethylchloroformate (FMOC) precolumn derivatization and a separation by HPLC with fluorometric detection. The selectivity is satisfactory enough to control ERY and OLE residues as not many interfering peaks are observed for various food matrices. The macrolides recoveries of the total procedure were low, although >50%. However, addition of an internal standard (roxithromycin) corrected for recovery to give satisfactory quantitative results for repeatability, linearity, detection and quantification limits and mainly accuracy.

Animals↗
PubMed2001

Functional analysis of OleY L-oleandrosyl 3-O-methyltransferase of the oleandomycin biosynthetic pathway in Streptomyces antibioticus.

Oleandomycin, a macrolide antibiotic produced by Streptomyces antibioticus, contains two sugars attached to the aglycon: L-oleandrose and D-desosamine. oleY codes for a methyltransferase involved in the biosynthesis of L-oleandrose. This gene was overexpressed in Escherichia coli to form inclusion bodies and in Streptomyces lividans, producing a soluble protein. S. lividans overexpressing oleY was used as a biotransformation host, and it converted the precursor L-olivosyl-erythronolide B into its 3-O-methylated derivative, L-oleandrosyl-erythronolide B. Two other monoglycosylated derivatives were also substrates for the OleY methyltransferase: L-rhamnosyl- and L-mycarosyl-erythronolide B. OleY methyltransferase was purified yielding a 43-kDa single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The native enzyme showed a molecular mass of 87 kDa by gel filtration chromatography, indicating that the enzyme acts as a dimer. It showed a narrow pH range for optimal activity, and its activity was clearly stimulated by the presence of several divalent cations, being maximal with Co(2+). The S. antibioticus OleG2 glycosyltransferase is proposed to transfer L-olivose to the oleandolide aglycon, which is then converted into L-oleandrose by the OleY methyltransferase. This represents an alternative route for L-oleandrose biosynthesis from that in the avermectin producer Streptomyces avermitilis, in which L-oleandrose is transferred to the aglycon by a glycosyltransferase.

Anti-Bacterial Agents↗
PubMed1990

[The use of the protoplast method for the selection of oleandomycin producers].

The use of protoplasting with subsequent reversion to the cellular form in improvement of the oleandomycin-producing organism provided a 110% increase in the range of culture variation with respect to the antibiotic production property. A regenerant with a potency of 12 to 20 per cent higher than that of the initial strain which produced 30 per cent lower amounts of dark pigments of melanin nature was isolated. Repeated protoplasting and regeneration of the regenerant provided a very low regeneration frequency i.e. 0.0002%. The potency of all the secondary regenerants was low.

Cell Count↗
PubMed1989

[Mutagenic effect of mitomycin C on different strains of oleandomycin producer Streptomyces antibioticus].

Mitomycin C, a DNA-tropic antibiotic, was shown to have a lethal effect on spore sprouts of two strains of Streptomyces antibioticus, an organism producing oleandomycin. When the time of exposure to the antibiotic increased there was an almost equal decrease in the survival rate. The mutagen action on the morphological variation and antibiotic production of the two closely related strains were diverse due to their genetic differences. The strain isolated after the culture treatment with a chemical mutagen and subjected to a more prolonged maintaining selection showed lower variation with respect to its colony morphology. The other strain isolated after treatment of the culture with high concentrations of its own antibiotic showed lower variation with respect to its antibiotic production property. The shift in the antibiotic production in the direction of the low active variants was characteristic of the both highly productive strains.

Colony Count, Microbial↗
PubMedDate not supplied

[Inhibition of oleandomycin synthesis by glucoses added during fermentation].

Oleandomycin biosynthesis by Streptomyces antibioticus is repressed by glucose added to the growth medium in the process of fermentation. Phosphotransferase involved in the synthesis of acetyl CoA and propionyl CoA (the precursors of the antibiotic macrolactone ring) is neither inhibited nor repressed, and the substrate specificity of the enzyme does not change. The content of cAMP in the mycelium of S. antibioticus does not change significantly when either glucose or sucrose is added to the medium 24 h after the inoculation whereas the content of exogenous cAMP rises abruptly 24 h after glucose addition. At the same time, the medium becomes much more acidic and the content of protein in the mycelium rises noticeably. Consequently, cAMP may be involved in the regulation of the culture growth.

Culture Media↗
PubMedDate not supplied

[Effect of surface-active agents (tween-21) on indices of energy metabolism in oleandomycin producers].

The specific growth rate of Streptomyces antibioticus, a producer of oleandomycin, and the specific rate of the antibiotic accumulation in the culture medium during fermentation were investigated. On the basis of the results obtained the fermentation period was divided into 7 phases of development. The culture treated with the surfactant (Tween-21) is characterized by a higher specific growth rate during the whole fermentation and a higher specific rate of the antibiotic accumulation at the stage of the highest production as compared to the control. The ATP content, the value of the adenylate energy charge and the contents of high-molecular weight polyphosphates in the mycelium were examined. In the phase of the intensive growth St. antibioticus was characterized by a higher ATP level and a higher energy charge. More active accumulation of polyphosphates was observed in the late intensive growth phase. It was also found that after the treatment of the culture with Tween-21 it utilized polyphosphates more actively during the antibiotic biosynthesis.

Culture Media↗
PubMed1987

[Characteristics of the oleandomycin producer inoculum at various levels of antibiotic biosynthesis].

Parameters of the oleandomycin-producing organism metabolism were studied at the stage of inoculum when intensity of the antibiotic biosynthesis was increased by treating the spores with a surface active substance (twin-21). It was shown that the inoculum producing later at the stage of fermentation higher quantities of the antibiotic was characterized by certain peculiarities. In particular, there were observed a shorter lag phase, a higher specific growth rate and a higher rate of accumulating the medium components at lower pyruvate levels in the exponential phase, higher activity of succinate dehydrogenase and higher levels of ATP in the mycelium during this period.

Fermentation↗
PubMed1987

[Polysaccharide composition of the cell wall of Streptomyces antibioticus RIA-594(39), a producer of the antibiotic oleandomycin].

The main polysaccharide components of the cell wall in S. antibioticus RIA-594 (39) i.e. peptidoglycan, teichoic acid and polysaccharide were studied. Peptidoglycan consists of the polysaccharide fraction containing equimolar quantities of N-acetylglucosamine and muramic acid and the peptide subunits including alanine, glutamic and L,L-diaminopimelic acids and glycine at a ratio of 1.4:0.9:1:0.9. It is characteristic that certain peptide subunits of the streptomycete contain no alanine. A polysaccharide differing from glycerol teichoic acid and containing galactose and N-acetylglucosamine was isolated from the cell wall. During the streptomycete development the quantity of peptidoglycan remained constant, the quantity of teichoic acid lowered and the quantity of polysaccharide increased. Correlation between the presence of aminosugars in the composition of teichoic acid and polysaccharide specific of the streptomycete cell wall and the presence of aminosugars in the structure of oleandomycin was shown. This is probably connected with characteristic features of the organism physiology.

Amino Acids↗
PubMed1987

[Effect of surface-active substances on carbohydrate metabolism in the producer of oleandomycin].

Activity of glucose-6-phosphate dehydrogenase (I), fructose diphosphate aldolase (II) and succinate dehydrogenase (III) and content of pyruvate (IV) in the mycelium of the oleandomycin-producing organism were studied during increased intensity of the antibiotic synthesis. The increase in the intensity of the antibiotic synthesis was induced by exposure of the spores to a surface active substance, twin-21. After the exposure a rise in the activity of all the three enzymes in the phase of the culture intensive growth was observed. During the antibiotic intensive production the cultures with increased antibiotic production levels were characterized by significantly higher activity of I as compared to the control while the activity levels of II and III were approximately the same. It was shown that concentration of IV in the mycelium during the antibiotic intensive biosynthesis decreased and the decrease was more pronounced after exposure to twin-21.

Carbohydrate Metabolism↗
PubMed1986

[Changes in the anatomic structures and cellular composition of lymph nodes after prenatal exposure to oleandomycin].

Tracheobronchial and mesenteric lymph nodes have been investigated in 120 embryos, fetuses and newborn (5-, 14-, 30-day-old) rats by means of anatomical, histological and electron microscopical methods. Prenatal influence of oleandomycin phosphate on development of lymph nodes has been analysed. Effect of the drug on the mother--fetus system produces certain reactive changes in the anatomical structures responsible for the barrier-filtration and drainage functions of the lymph nodes. The immunocytopoietic function is inhibited, as demonstrates certain decrease of lymphatic line cells.

Animals↗
PubMed1977

A comparison of the effect of oleandomycin and oxytetracycline supplementation on the growth and the meat quality of Dokki-4 chicks reared in hot weather.

1000 chickens were used to investigate up to 24 weeks under high environmental temperatures the addition of different types (oxytetracycline and oleandomycin) and different levels (5 or 20 ppm) of antibiotics to the basal diet. Supplementation with 20 ppm had--with both types of antibiotics--a marked positive effect on the growth rate and various quality characteristics of the products. The effect was higher in male animals than in females.

Animal Feed↗
PubMed1983

[Parameters characterizing the productivity of an inoculum of the producer of oleandomycin].

The possibility of using different criteria for estimation of the productivity of the vegetative inoculum of the oleandomycin-producing organism was studied with a purpose of providing maximum levels of the biosynthetic process. The use of the criteria of the culture respiration intensity and accumulation of the physiologically active mycelium as the main ones was shown to be advisable. The quantity and distribution of the mycelium in samples and the time course of changes in active acidity of the medium during the inoculum growth may be used as auxiliary criteria.

Hydrogen-Ion Concentration↗
PubMed1976

Quantitative and qualitative determinations of the combined effect of tetracycline and oleandomycin. I. In vitro effect.

Growth inhibitory effect of combined treatment of tetracycline (TC) and oleandomycin (OM), at a ratio of 2:1, on certain species of pathogenic bacteria including drug-resistant ones was examined. By the crossed paper strip method, synergistic effects were demonstrated against 9 of the 16 strains of Staphylococcus aureus, and all of the 5 strains of Escherichia coli studied. Antagonism was observed with none of the strains and with 2 strains of Streptococcus pyogenes and 2 strains of Streptococcus pneumoniae tested in the present experiments. The MICs determined by the agar dilution method, also gave similar results, although synergism was not conclusively demonstrated by this method. With representative strains of S. aureus, synergism was evidenced by quantitative measurement of growth inhibition. In some strains, 1.0 mug of one drug per ml of medium inhibited the induction of resistance to the second drug. Such a small dose of one drug also inhibited the development of a mutant resistant to the second drug. These inhibitory actions were thought to be one of the important factors causing the synergistic effect of TC and OM on drug resistant bacteria.

Drug Combinations↗