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At least 19 recordsLinked to original sources
PubMed1990

Selection of Streptomyces ambofaciens mutants that produce large quantities of spiramycin and determination of optimal conditions for spiramycin production.

The aim of this work was to develop a strategy to isolate a morphologically stable mutant of Streptomyces ambofaciens ATCC 15154 which produced high titers of spiramycin. The rationale was to grow a nitrosoguanidine-mutated population for many generations under nonselective conditions followed by two cycles of protoplast formation and regeneration. A total of 2,400 surviving colonies were then screened for spiramycin production and subsequently checked for stability. From this experiment, strain 6-37 was isolated that produced 181 mg of spiramycin per liter and only one morphological type. The parent strain (ATCC 15154) produced 107 mg of spiramycin per liter and four morphological types. Strain 6-37 was then mutated with nitrosoguanidine, and 14,000 colonies were screened for spiramycin production. From this experiment, five strains were isolated that produced titers ranging from 187 to 373 mg of spiramycin per liter. Subsequent media and time studies with these strains resulted in a fermentation that produced 1,728 mg of spiramycin per liter.

Biotechnology↗
PubMed1978

Evaluation of spiramycin as a therapeutic agent for elimination of nasopharyngeal pathogens. Possible use of spiramycin for middle ear infections and for gonococcal and meningococcal nasopharyngeal carriage.

Varying doses of spiramycin were administered orally to healthy volunteers, and concentrations in serum and saliva were determined. The absorption of the drug was not significantly influenced by concomitant food intake. Saliva peak concentrations were 1.3--4.8 times higher than peak concentrations in serum. The elimination half life was 2--3 h in serum, and 4--8 h in saliva. Accumulation of the drug was seen in saliva but not in serum. The possible effect of spiramycin in eliminating bacteria from the nasopharynx was evaluated in vitro by comparing the spiramycin saliva concentrations with the MICs of bacteria known to establish themselves in the nasopharynx. At a concentration of 1.2 microgram/ml, spiramycin inhibited all investigated strains of group A streptococci, pneumococci and Branhamella catarrhalis, and at 2.4 microgram/ml all investigated gonococci. Concentrations of 19 and 38 microgram/ml, respectively, were required to inhibit all meningococci and Haemophilus influenzae. Following administration of 1.5 g spiramycin as a single daily dose for 3 days, the mean concentration in saliva reached or surpassed the MIC values of streptococci, pneumococci and Branhamella for 45 h, and of gonococci for 25 h. The possible use of spiramycin for prevention of relapses in acute otitis media and in treatment of serous otitis media is discussed, as well as the possible use of the drug in gonococcal and meningococcal nasopharyngeal carriage.

Acute Disease↗
PubMed1990

Cloning of spiramycin biosynthetic genes and their use in constructing Streptomyces ambofaciens mutants defective in spiramycin biosynthesis.

Several cosmid clones from Streptomyces ambofaciens containing the spiramycin resistance gene srmB were introduced into S. fradiae PM73, a mutant defective in tylosin synthesis, resulting in tylosin synthesis. The DNA responsible for this complementation was localized to a 10.5-kilobase EcoRI fragment. A 32-kilobase DNA segment which included the srmB spiramycin resistance gene and DNA which complemented the defect in strain PM73 were mutagenized in vivo with Tn10 carrying the gene for Nmr (which is expressed in Streptomyces spp.) or in vitro by insertional mutagenesis with a drug resistance gene (Nmr) cassette. When these mutagenized DNA segments were crossed into the S. ambofaciens chromosome, three mutant classes blocked in spiramycin synthesis were obtained. One mutant accumulated two precursors of spiramycin, platenolide I and platenolide II. Two mutants, when cofermented with the platenolide-accumulating mutant, produced spiramycin. Tylactone supplementation of these two mutants resulted in the synthesis of a group of compounds exhibiting antibiotic activity. Two other mutants failed to coferment with any of the other mutants or to respond to tylactone supplementation.

Chromosomes, Bacterial↗
PubMed1986

[Curative activity of spiramycin adipate by parenteral route in experimental septicemia in mice. Comparison with orally administered basic spiramycin].

Experimental septicemia was induced in mice by intraperitoneal injection of 10 to 100 lethal doses of Staphylococcus aureus and Streptococcus pneumoniae. Animals were treated by a mixture of adipic acid and spiramycin (subcutaneous route) or by spiramycin base (oral route), 1 and 6 hours after infection. To determine the effective dose 50% that achieves survival of half the mice after 7 days, each drug was used in 6 dosages (mg/kg) and each dosage was given to 12 mice. In 21 independent experiments, ED50S of spiramycin adipate by the subcutaneous route were found to be 5 to 50 times lower than those of spiramycin base per os. These results are consistent with the high serum peak concentrations of spiramycin adipate observed following subcutaneous administration.

Adipates↗
PubMed1984

Chemical modification of spiramycins. III. Synthesis and antibacterial activities of 4''-sulfonates and 4''-alkylethers of spiramycin I.

Among the derivatives protected with t-butyldimethylsilylether of spiramycin I, 2'-O-acetylspiramycin I 3,18-(O-t-butyldimethylsilyl)acetal was found to be a suitable intermediate for 4''-modification of spiramycin I. Seven 4''-sulfonates and four 4''-alkylethers were synthesized, which were more active against bacteria in vitro than spiramycin I. 4''-Substituted derivatives with relatively small sulfonyl and alkyl groups were comparable in therapeutic effect to spiramycin I.

Animals↗
PubMed1999

Dispensable ribosomal resistance to spiramycin conferred by srmA in the spiramycin producer Streptomyces ambofaciens.

Streptomyces ambofaciens produces the macrolide antibiotic spiramycin, an inhibitor of protein synthesis, and possesses multiple resistance mechanisms to the produced antibiotic. Several resistance determinants have been isolated from S. ambofaciens and studies with one of them, srmA, which hybridized with ermE (the erythromycin-resistance gene from Saccharopolyspora erythraea), are detailed here. The nucleotide sequence of srmA was determined and the mechanism by which its product confers resistance was characterized. The SrmA protein is a methyltransferase which introduces a single methyl group into A-2058 (Escherichia coli numbering scheme) in the large rRNA, thereby conferring an MLS (macrolide-lincosamide-streptogramin type B) type I resistance phenotype. A mutant of S. ambofaciens in which srmA was inactivated was viable and still produced spiramycin, indicating that srmA is dispensable, at least in the presence of the other resistance determinants.

Anti-Bacterial Agents↗
PubMed1985

Chemical modification of spiramycins. VI. Synthesis and antibacterial activities of 3,3''-di-O-acyl-4''-O-sulfonyl and 3,3''-di-O-acyl-4''-O-alkyl derivatives of spiramycin I.

3,3''-Di-O-acyl-4''-O-sulfonyl and 3,3''-di-O-acyl-4''-O-alkyl derivatives of spiramycin I were synthesized and evaluated by four parameters, antibacterial activity, affinity to ribosomes, lypophilicity and therapeutic effects. Among them, 3,3''-di-O-acetyl-4''-O-mesyl and 3,3''-di-O-acetyl-4''-O-methylspiramycin I having relatively small substituents at 4''-position were the most effective in mouse protection tests, and the results were comparable to acetylspiramycin.

Animals↗
PubMed1993

Resistance to spiramycin in Streptomyces ambofaciens, the producer organism, involves at least two different mechanisms.

During its stationary phase, Streptomyces ambofaciens produces the macrolide antibiotic spiramycin, and has to protect itself against this antibiotic. Young mycelia, not yet producing spiramycin, are sensitive to it, but they become fully resistant when production begins. In a sensitive mycelium, resistance could be induced by exposure to sub-inhibitory concentrations of spiramycin, and these induced mycelia, like producing mycelia were resistant not only to spiramycin but also to several other macrolide antibiotics. Ribosomes extracted from these resistant mycelia were shown in vitro to be more resistant to spiramycin than ribosomes extracted from sensitive mycelium, indicating that S. ambofaciens possesses a spiramycin-inducible ribosomal resistance to spiramycin and to macrolide antibiotics. Studies with spiramycin non-producing mutants showed that, in these mutants, resistance to spiramycin also varies during cultivation, in that an old culture was much more resistant than a young one. But with these non-producing mutants, the spectrum of resistance was narrower, and in vitro data showed that resistance was not due to ribosomal modification. These results suggest that S. ambofaciens presents at least two distinct mechanisms for spiramycin resistance; a spiramycin-inducible ribosomal resistance, and a second resistance mechanism which might be temporally regulated and which could involve decreased permeability to, or export of, the antibiotic. The two mechanisms are probably at work simultaneously in the producing mycelium, the spiramycin-inducible resistance being induced by endogenous spiramycin. In non-producing mutants, in the absence of self-induction by spiramycin, only the second mechanism is observed.

Anti-Bacterial Agents↗
PubMed1988

Pharmacokinetics of spiramycin in man.

The pharmacokinetics of spiramycin were studied after single and repeated administration by iv and oral routes. Following iv administration of a 500-mg dose in a one-hour infusion, peak serum concentrations were 1.54-3.10 mg/l. These concentrations are higher than MICs of spiramycin for various infectious agents. Eight hours after the end of infusion, the mean serum concentration was close to 0.25 mg/l. Spiramycin is rapidly and widely distributed throughout the body and achieves high ratios of tissue to serum concentrations in bucco-dental, pulmonary and prostatic tissues and skin. The distribution half-life of spiramycin was 10 min. The steady-state volume of distribution (Vdss) and the tissue distribution volume were 5.6 and 4.5 l/kg. The absolute bioavailability of spiramycin was 36% (S.D. +/- 14). Oral doses of spiramycin between 1 and 2 g resulted in linear increase in the peak serum levels and areas under the serum concentration-time curve. Spiramycin does not appear to undergo important metabolic conversion and is mainly excreted via the biliary route. Indeed, in man, the urinary excretion of active compounds represents only 7.6 to 20% of the administered dose. Spiramycin had a terminal elimination half-life of approximately 5 h. Renal clearance (144 ml/min) was much lower than non-renal clearance (887 ml/min). The total body clearance of spiramycin in young adults was 1.42 l/min (S.D. +/- 0.5) but only 0.53 l/min (S.D. +/- 14) in elderly subjects. During repeated iv administration (500 mg tid), steady state was achieved after four doses. Cmax and Cmin were 3.0 and 0.5 mg/l in young adults and 4.5 and 1.75 mg/l in elderly patients. Spiramycin's kinetics differ in several important respects from erythromycin's, notably the larger volume of distribution of spiramycin which reflects the higher tissue concentration. The reduced spiramycin clearance in elderly subjects requires further investigation.

Administration, Oral↗
PubMed1998

Pharmacodynamics and pharmacokinetics of spiramycin and their clinical significance.

The absolute bioavailability of oral spiramycin is generally within the range of 30 to 40%. After a 1 g oral dose, the maximum serum drug concentration was found to be within the range 0.4 to 1.4 mg/L. The tissue distribution of spiramycin is extensive. The volume of distribution is in excess of 300 L, and concentrations achieved in bone, muscle, respiratory tract and saliva exceed those found in serum. The intracellular penetration of spiramycin is also rapid and extensive, with the concentrations in alveolar macrophages 10 to 20 times greater than simultaneous serum concentrations. Spiramycin is less metabolised than some of the other macrolides. The renal excretion of spiramycin is low, with 4 to 20% of the dose being excreted by this route. High concentrations of spiramycin are achieved in bile, which is an important route of elimination. The serum elimination half-life of spiramycin is between 6.2 and 7.7 hours. Of significance to clinicians may be the finding that spiramycin is highly concentrated in the respiratory tract and other tissues and macrophages. The post-antibiotic effect of spiramycin is significant and this effect is more prolonged than that of erythromycin against Staphylococcus aureus. Spiramycin has also been shown to greatly reduce the capacity of strains of Gram-positive cocci to adhere to human buccal cells.

Animals↗
PubMed1988

Spiramycin uptake by alveolar macrophages.

The in-vitro and in-vivo uptake of spiramycin by human and animal alveolar macrophages was studied. In-vitro penetration was studied in guinea pig and human alveolar macrophages incubated in medium 199 at 37 degrees C containing spiramycin at various concentrations. Results were expressed as the cellular/extracellular concentration ratio (C/E). The in-vivo study was performed in patients receiving 500 or 1000 mg spiramycin every 8 h as a 1-h infusion on day 1. A single infusion was given on day 2, 2 h before serum and bronchoalveolar lavage (BAL) sampling. Spiramycin was assayed by HPLC, and by a microbiological assay. In guinea pig alveolar macrophages, the C/E ratio of spiramycin after 60 min at 37 degrees C was 20.3 +/- 6.5 when the concentration was 10 mg/l. In human alveolar macrophages, the C/E ratio was 21.3 +/- 8.7 at 5 mg/l spiramycin and 23.8 +/- 8.7 at 50 mg/l. The accumulated spiramycin was slowly released when the cells (guinea pig alveolar macrophages) were washed and re-incubated in antibiotic free medium. Spiramycin was able to penetrate the alveolar space. In BAL supernatant, spiramycin levels were about 24-fold the serum level (n = 6 patients), when the BAL/serum glucose ratios were used as the dilution estimate. Alveolar macrophage levels ranged from 17 to 210 mg/l (n = 6 patients receiving 500 mg spiramycin infusion). These results are consistent with the in-vitro data.

Animals↗