Showing papers in "The Journal of Antibiotics in 1984"
TL;DR: Investigation of the antimicrobial spectrum of epsilon-poly-L-lysine found it to be optimum for antimicrobial activity, and studies on the mode of action suggest that absorption of ePSilon-PL to the bacterial cell surface plays an important role in its antibacterial activity.
Abstract: The antimicrobial spectrum of epsilon-poly-L-lysine (n = 25-30, epsilon-PL) was investigated by comparison with alpha-poly-L-lysine (n = 50, alpha-PL) epsilon-PL showed antimicrobial activity against Gram-positive and -negative bacteria at concentrations of 1-8 micrograms/ml alpha-PL was less active than epsilon-PL A chain length of at least 10 L-lysine monomers was found to be optimum for antimicrobial activity Chemical modification of the amino groups of epsilon-PL lowered its antibacterial activity Studies on the mode of action of epsilon-PL suggest that absorption of epsilon-PL to the bacterial cell surface plays an important role in its antibacterial activity
439 citations
TL;DR: In the active dose range, rapamycin appeared less toxic than the other drugs and compatible with 5-fluorouracil and cyclophosphamide, and upon oral administration, its activity was reduced but not abolished.
Abstract: Rapamycin exhibits activity against several ascites and solid transplantable tumors; it is slightly active to inactive against leukemias. On a weight basis, rapamycin was less active than 5-fluorouracil, cyclophosphamide and adriamycin, but rapamycin's maximal activity against Colon 38 tumor was similar to that of 5-fluorouracil and cyclophosphamide. Its activity was such that it significantly inhibited tumor growth at any stage of development. In the active dose range, rapamycin appeared less toxic than the other drugs. In the Colon 38 tumor model, rapamycin at a given dose exhibited the same activity when administered ip, iv, im and sc; upon oral administration, its activity was reduced but not abolished. Rapamycin was compatible with 5-fluorouracil and cyclophosphamide. The sequential treatment 5-fluorouracil-rapamycin-cyclophosphamide was superior to the sequence 5-fluorouracit-adriamycin-cyclophosphamide in protecting Colon 38 tumor-bearing mice. 29-Demethoxyrapamycin exerted only marginal activity against P388 lymphocytic leukemia; it was inactive against B16 melanocarcinoma and Colon 38 solid tumor.
326 citations
TL;DR: The bafilomycins A1, A2, B1, B2, C1 and C2, a new type of macrolide antibiotics with a 16-membered lactone ring, were isolated from the fermentation broth of three Streptomyces griseus strains by ethyl acetate extraction and column chromatography on silica gel.
Abstract: The bafilomycins A1, A2, B1, B2, C1 and C2, a new type of macrolide antibiotics with a 16-membered lactone ring, were isolated from the fermentation broth of three Streptomyces griseus strains (TU 1922, TU 2437, TU 2599) by ethyl acetate extraction and column chromatography on silica gel. The bafilomycins exhibit activity against Gram-positive bacteria and fungi. Physico-chemical data, chemical structures and biological activities are reported.
297 citations
TL;DR: The therapeutic efficacies of TE-031 and TE-032 against systemic and subcutaneous infections provoked by Gram-positive bacteria in mice are 4- to 35-fold superior to those of EM and JM.
Abstract: The in vitro and in vivo antibacterial activities of 6-O-methylerythromycin A (TE-031, A-56268, or clarithromycin) and 6, 11-di-O-methylerythromycin A (TE-032) have been compared with those of erythromycin A (EM) and josamycin (JM). TE-031 and TE-032, having the same antibacterial spectra as EM, are active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, L-form bacteria and Mycoplasmapneumoniae. The activity of TE-031 against clinical isolates is equal to or two times more potent than that of EM, whereas TE-032 is slightly less active than EM. The activities of TE-031 and TE-032 are pH dependent (more active at pH 8 than at 5) and are increased by adding serum to medium. TE-031 and TE-032 show dose-related bactericidal activities against Haemophilus influenzae. The therapeutic efficacies of TE-031 and TE-032 against systemic and subcutaneous infections provoked by Gram-positive bacteria in mice are 4- to 35-fold superior to those of EM and JM. TE-031 and TE-032 have demonstrated higher and longer-lasting plasma levels than EM when administered orally to mice, rats or dogs.
250 citations
171 citations
TL;DR: Valiolamine has more potent alpha-glucosidase inhibitory activity against porcine intestinal sucrase, maltase and isomaltase than valienamine, validamine and hydroxyvalidamine which were reported as building blocks of validamycins and microbial oligosaccharide alpha- glucosIDase inhibitors.
Abstract: Valiolamine, a new aminocyclitol has been isolated from the fermentation broth of Streptomyces hygroscopicus subsp. limoneus and its structure has been determined to be (1(OH),2,4,5/1,3)-5-amino-1-C-(hydroxymethyl)-1,2,3,4-cyclohexanetetr ol. Valiolamine has more potent alpha-glucosidase inhibitory activity against porcine intestinal sucrase, maltase and isomaltase than valienamine, validamine and hydroxyvalidamine which were reported as building blocks of validamycins and microbial oligosaccharide alpha-glucosidase inhibitors. In addition, valienamine, validamine and hydroxyvalidamine have been isolated from the fermentation broth.
159 citations
TL;DR: Results of preliminary studies indicating that CC-1065 caused lethal delayed hepatotoxicity at therapeutic antineoplastic doses to mice bearing a variety of transplantable tumors and in the rabbit are shown.
Abstract: It was previously shown that the potent new DNA-binding antibiotic, CC-1065, prolonged life span, but was not curative, when administered to mice bearing a variety of transplantable tumors. In this paper we show results of preliminary studies indicating that CC-1065 caused lethal delayed hepatotoxicity at therapeutic antineoplastic doses. In non-tumor-bearing mice toxic deaths were delayed ca 50 days after a single iv dose of 12.5 micrograms/kg and as much as 70 days after 10 micrograms/kg was given ip. Intravenous mouse LD50's were 9 micrograms/kg, single dose, and 0.3 microgram/kg/day, five daily doses. Intraperitoneal LD50's were 0.53 approximately 6.90 micrograms/kg, single dose, and 0.14 microgram/kg/day, five daily doses. Mice treated with high doses iv died within 12 days with frank hepatic necrosis, whereas delayed deaths at lower doses were associated with changes in hepatic mitochondrial morphology. This suggested that separate mechanisms of hepatotoxicity were operative at high and low dose ranges. Attempts to prevent the delayed toxicity of CC-1065 in the mouse by treatment with WR-2721, N-acetylcysteine, phenobarbital, Aroclor 1254, and 3-methylcholanthrene were unsuccessful; no effect on the LD50 or the times of death was observed. Lethal doses in the rabbit were similar on a body surface area basis to those in the mouse; evidence of hepatotoxicity was also observed in the rabbit.
150 citations
TL;DR: A new 16-membered macrolide designated as rhizoxin was isolated as a toxin produced by Rhizopus chinensis, the causal agent of rice seedling blight, and exhibited potent antifungal activity but little effect against bacteria.
Abstract: A new 16-membered macrolide designated as rhizoxin was isolated as a toxin produced by Rhizopus chinensis, the causal agent of rice seedling blight. The skeletal structure was determined by detailed NMR spectroscopic investigation of this compound and of its derivatives. Rhizoxin induced at a concentration of 10 ng/ml abnormal swelling of rice seedling roots, which is one of the characteristic symptoms of this disease. This compound also exhibited potent antifungal activity but little effect against bacteria.
145 citations
TL;DR: Teichomycin (teicoplanin) was found to be a mixture of five closely related components of similar polarity and of one more polar component, designated T-A3, which has the same molecular size but differs in a side aliphatic chain.
Abstract: Teichomycin (teicoplanin) was found to be a mixture of five closely related components of similar polarity, designated T-A2-1, 2, 3, 4 and 5 and of one more polar component, designated T-A3 The separation of the single components was achieved by reverse phase partition chromatography and their physico-chemical and biological properties were compared The results show that 1) the five major components have the same molecular size of about 1,900; 2) they contain the same ionization function, ie, a carboxyl group and an amino group which form a zwitterion, and four phenolic groups; 3) they differ in a side aliphatic chain The component T-A3 is not described
139 citations
TL;DR: Actinoplanes sp. ATCC 33076 is a new strain that was found to produce an antibiotic, designated A-16686, which is a complex of three closely-related polypeptides containing chlorinated phenyl moieties and D-mannose as mentioned in this paper.
Abstract: Actinoplanes sp. ATCC 33076 is a new strain that was found to produce an antibiotic, designated A-16686, which is a complex of three closely-related polypeptides containing chlorinated phenyl moieties and D-mannose. Both the complex and the single fractions possess a good activity against Gram-positive bacteria. A-16686 specifically inhibits the synthesis of the bacterial cell wall.
118 citations
TL;DR: LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity and caused severe damage to the C. albicans cell.
Abstract: LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25μg/ml, respectively. Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5% LY121019 was as effective as 3% nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histamine-like reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog.
TL;DR: Concanamycins A, B and C were isolated from the mycelium of Streptomyces diastatochromogenes S-45 as effective inhibitors of the proliferation of mouse splenic lymphocytes stimulated by concanavalin A, and are biologically active in vitro against several fungi and yeasts, but not against bacteria.
Abstract: Concanamycins A, B and C were isolated from the mycelium of Streptomyces diastatochromogenes S-45 as effective inhibitors of the proliferation of mouse splenic lymphocytes stimulated by concanavalin A. They represent a new class of 18-membered macrolide antibiotics, and are biologically active in vitro against several fungi and yeasts, but not against bacteria. Concanamycin A, the main component, has been identified with antifungal antibiotics, folimycin and A-661-I.
Journal Article•
TL;DR: A new strain that was found to produce an antibiotic, designated A-16686, which is a complex of three closely-related polypeptides containing chlorinated phenyl moieties and D-mannose, possesses a good activity against Gram-positive bacteria.
Abstract: Actinoplanes sp. ATCC 33076 is a new strain that was found to produce an antibiotic, designated A-16686, which is a complex of three closely-related polypeptides containing chlorinated phenyl moieties and D-mannose. Both the complex and the single fractions possess a good activity against Gram-positive bacteria. A-16686 specifically inhibits the synthesis of the bacterial cell wall.
TL;DR: The results obtained indicate that E. coli BM2195 resists erythromycin by the production of an eryTHromycin esterase which hydrolyzes the lactone ring of the antibiotic.
Abstract: Escherichia coli BM2195 is highly resistant to erythromycin by inactivation of the antibiotic. We have determined the structure of the modified antibiotic by physico-chemical techniques including mass spectrometry, infrared spectrophotometry, 13C nuclear magnetic resonance, and circular dichroism. The results obtained indicate that E. coli BM2195 resists erythromycin by the production of an erythromycin esterase which hydrolyzes the lactone ring of the antibiotic.
TL;DR: The complete structures of bacillomycin D and bacilomycin L were revised by FAB mass spectrometry and by Edman degradation of the derivatives resulting from the N-bromosuccinimide reaction.
Abstract: The complete structures of bacillomycin D and bacillomycin L were revised by FAB mass spectrometry and by Edman degradation of the derivatives resulting from the N-bromosuccinimide reaction. The homologous components of both series of antibiotics were separated by HPLC and the beta-amino acids were identified by capillary gas chromatography.
TL;DR: The catalytic properties of the partially purified deacetoxycephalosporin C (DAOC)-synthetase and DAOC-hydroxylase from an industrial strain of Cephalosporium acremonium were studied and direct evidence was obtained from SDS-polyacrylamide gel electrophoresis that the two reactions are catalyzed by a single enzyme.
Abstract: The catalytic properties of the partially purified deacetoxycephalosporin C (DAOC)-synthetase and DAOC-hydroxylase from an industrial strain of Cephalosporium acremonium were studied. After mechanical breakage of the cells, purification was achieved by fractional (NH4) 2SO4 precipitation, gel chromatography on Sephadex G-75, ion exchange chromatography on DEAE-Trisacryl M and two isoelectric focusing steps. The two enzyme activities could not be separated. Indirect evidence was obtained from SDS-polyacrylamide gel electrophoresis of the purest fractions obtained by isoelectric focusing that the two reactions are catalyzed by a single enzyme with a molecular weight of 33, 000±2, 000 and a pI of 4.6±0.1. Both reactions require α-ketoglutarate, FeSO4, ascorbate and O2, whereas additional ATP shows only a slight stimulation.
TL;DR: Two new acetylenic antibiotics, cepacins A and B, have been isolated from the fermentation broth of Pseudomonas cepacia SC 11,783 and assigned structures 1 and 2.
Abstract: Two new acetylenic antibiotics, cepacins A and B, have been isolated from the fermentation broth of Pseudomonas cepacia SC 11,783 and assigned structures 1 and 2. Cepacin A has good activity against staphylococci (MIC 0.2 micrograms/ml) but weak activity against streptococci (MIC 50 micrograms/ml) and the majority of Gram-negative organisms (MIC values 6.3 approximately greater than 50 micrograms/ml). Cepacin B has excellent activity against staphylococci (MIC less than 0.05 micrograms/ml) and some Gram-negative organisms (MIC values 0.1 approximately greater than 50 micrograms/ml).
TL;DR: An antibiotic activity was extracted from the cell mass of the myxobacterium, Stigmatella aurantiaca strain Sg a15, and appears to be a new antibiotic, and was named stigmatellin.
Abstract: An antibiotic activity was extracted from the cell mass of the myxobacterium, Stiginatella aurantiaca strain Sg a15. The antibiotic was toxic for yeasts and filamentous fungi, but not for most bacteria. The compound had the molecular formula C30H42O7, appears to be a new antibiotic, and was named stigmatellin. In addition to stigmatellin, the strain produced relatively large quantities of a second, structurally unrelated antibiotic, a mixture of three myxalamid homologues.
TL;DR: Quantitative determination of sugars obtained by degradative reactions and NMR/LC-MS studies on suitable derivatives confirmed that all the components carry one N-acyl-D-glucosamine and that at least two of them are characterized by N-decanoyl and N-undecanoysl chains on the D-gl Sucosamine unit.
Abstract: Teicoplanin is an antibiotic complex consisting of five closely related factors, T-A2-1, 2, 3, 4 and 5 and a more polar factor, T-A3-1. By controlled acid hydrolysis the complex is transformed into pseudoaglycones and finally into a single aglycone with consecutive removal of three sugar units. Quantitative determination of sugars obtained by degradative reactions and NMR/LC-MS studies on suitable derivatives confirmed that all the components carry one N-acyl-D-glucosamine and that at least two of them are characterized by N-decanoyl and N-undecanoyl chains on the D-glucosamine unit. The hydrolysis products still possess in vitro and in vivo activity.
TL;DR: It is suggested that glucose represses but does not inhibit penicillin biosynthesis, as studied with resting cell cultures in which further protein synthesis was blocked with cycloheximide.
Abstract: The addition of glucose to batch cultures of Penicillium chrysogenum AS-P-78 reduced the biosynthesis of penicillin. This regulatory effect was also observed in penicillin biosynthesis by nitrogen-limited resting cells when cultures were previously grown in high concentrations of glucose. The effect of glucose was concentration-dependent in the range of 28-140 mM. Incorporation of L-[U-14C]valine into penicillin in nitrogen-limited resting cultures was reduced by 70% when cells were grown on 140 mM glucose, as compared with that grown on lactose. It was not affected when the sugar was added to the resting cell system, in which penicillin biosynthesis took place without growth. Fructose, galactose and sucrose exerted the regulatory effect to the same extent as glucose (64 to 70%). Lactose did not exert suppression of penicillin biosynthesis. Penicillin-synthesizing activity in control cultures with lactose reached a peak at 24 hours of incubation and decreased slowly thereafter, as studied with resting cell cultures in which further protein synthesis was blocked with cycloheximide. Glucose repressed the formation of penicillin-synthesizing enzymes, but had no effect on the activity of these enzymes. These results suggest that glucose represses but does not inhibit penicillin biosynthesis.
TL;DR: It is suggested that phosalacine was decomposed to provide phosphinothricin after its incorporation into microbial or plant cells, and exhibited the antimicrobial and herbicidal activities by inhibiting glutamine synthetase with phosphinOTHricin although phosalACine itself hardly inhibited the enzyme.
Abstract: Phosalacine, a new herbicidal antibiotic containing phosphinothricin was isolated from the culture filtrate of a soil isolate Kitasatosporia phosalacinea KA-338. It was a water soluble, amphoteric compound obtained as an amorphous powder (C14H28N3O6P, MW 365). The antibiotic exhibited antimicrobial activity against Gram-positive and Gram-negative bacteria and some fungi on a minimal medium and the activity was reversed by L-glutamine. It also showed herbicidal activity against alfalfa. It is suggested that phosalacine was decomposed to provide phosphinothricin after its incorporation into microbial or plant cells, and exhibited the antimicrobial and herbicidal activities by inhibiting glutamine synthetase with phosphinothricin although phosalacine itself hardly inhibited the enzyme.
TL;DR: The structures of 1 and 2 were determined to be 5-amino-5-deoxy-D-mannopyranose and D-mannonic-delta-lactam, respectively, on the basis of 1H NMR spectroscopy and X-ray structural analysis.
Abstract: A new aminosugar named nojirimycin B (1) has been isolated as its bisulfite adduct from the culture broth of Streptomyces lavendulae SF-425, together with nojirimycin. Microbiological oxidation of 1 with Gluconobacter suboxydans IAM 1829 gave a δ-lactam (2). The structures of 1and 2 were determined to be 5-amino-5-deoxy-D-mannopyranose and D-mannonic-δ-lactam, respectively, on the basis of 1H NMR spectroscopy and X-ray structural analysis. Both 1 and2 exhibited powerful inhibitory activity against rat epididymal α-mannosidase and apricot β-glucosidase.
TL;DR: Imipenem was shown to have very high binding affinities to PBPs-2 and -4 in E. coli and P. aeruginosa, and appreciable affinITIES to most of their other major PBPs, and seemed to cause strong inhibition of the transglycosylase activity of PBP-1A by some unknown mechanism.
Abstract: The binding affinities of imipenem (N- formimidoylthienamycin ) to penicillin-binding proteins ( PBSs ) of Escherichia coli and Pseudomonas aeruginosa were determined by two different methods in which competition with [14C]benzylpenicillin for the binding sites was measured. By both methods imipenem was shown to have very high binding affinities to PBPs-2 and -4 in E. coli and P. aeruginosa, and appreciable affinities to most of their other major PBPs. But higher concentrations of imipenem were required for binding to the PBPs-3 in these bacteria. More direct information about the antibacterial activity of imipenem was obtained by measuring its inhibition of the peptidoglycan-synthetic enzyme activities of E. coli PBPs. The results of enzyme inhibitions were compatible with those obtained in binding experiments. The antibiotic inhibited the transpeptidase activities of PBPs-1A, -1B and -2, and the D-alanine carboxypeptidase activities of PBPs-4 and -5. The antibiotic also seemed to cause strong inhibition of the transglycosylase activity of PBP-1A by some unknown mechanism. It inhibited the transpeptidase activity of PBP-3 only weakly, which is consistent with the findings that it had low binding affinity to PBP-3 and did not inhibit septum formation by the cells.
TL;DR: The chemical structure was elucidated as (2R,3S)-3-amino-2-oxetane carboxylic acid by analysis of the spectral data and by X-ray diffraction methods, which is the first natural product possessing an oxetane ring.
Abstract: A new amino acid-antimetabolite, oxetin, was isolated from a fermetation broth of a Streptomycesp .s OM-2317, a soil isolate, The chemical structure was elucidated as(2R, 3S)-3-amino-2-oxetane carboxylic acid by analysis of the spectral data and by X-ray diffraction methods. The antibiotic is the first natural product possessing an oxetane ring. Certain microorganisms were inhibited by oxetin only when cultivated in minimal media. The inhibitory action was reversed by several amino acids such as L-isoleucine, L-methionine, L-valine and L-glutamine. It also exhibited herbicidal activity and inhibited glutamine synthetase from spinach leaves.
TL;DR: It appears that the ring-expansion step is a very sensitive part of beta-lactam biosynthesis in C. acremonium with respect to nitrogen source repression and other enzymes may also be sensitive in view of the fact that nitrogen source derepression not only led to increases in cephalosporin C but, to a lesser extent, penicillin N and total beta- lactam titers.
Abstract: A variety of inorganic and organic nitrogen sources were added to fermentation media to determine their regulatory effects on the production of beta-lactam antibiotics by Cephalosporium acremonium. (NH4)2SO4 at concentrations higher than 100 mM (1.3%) strongly inhibited beta-lactam production. L-Asparagine and L-arginine proved to be the best nitrogen sources tested for beta-lactam production. The optimum concentration of asparagine was 1.2%. Higher concentrations led to NH3 accumulation, increase in pH, and lower growth rates. Addition of tribasic magnesium phosphate [Mg3(PO4)2 X 8H2O] to the (NH4)2SO4-containing medium stimulated beta-lactam production markedly and ammonium repression of the ring-expansion enzyme was reversed. It appears that the ring-expansion step is a very sensitive part of beta-lactam biosynthesis in C. acremonium with respect to nitrogen source repression. Other enzymes may also be sensitive in view of the fact that nitrogen source derepression not only led to increases in cephalosporin C but, to a lesser extent, penicillin N and total beta-lactam titers.
TL;DR: Cleavage of DNA by quinocarcin was inhibited by the addition of radical scavengers, superoxide dismutase and catalase suggesting that it is caused by generation of oxygen and/or hydroxyl free radicals.
Abstract: Quinocarcin is a colorless antibiotic that was discovered in the culture broths of Streptomyces melanovinaceus.1) The structures of quinocarcin and quinocarcinol (an inactive homologue) were elucidated by us2) and by HIRAYAMA et al.3) as shown in Fig. 1. Quinocarcin consists of the novel skeleton, 8,11-iminoazepinoisoquinoline and it showed antibacterial activity and antitumor activity.1) The mode of action was investigated, and the results are presented in this publication. Quinocarcin strongly inhibited incorporation of [3H]thymidine into Bacillus subtilis in vivo. Inhibition of DNA synthesis in B. subtilis was found to be due to inhibition of DNA polymerase reaction and cleavage of double stranded DNA. Cleavage of DNA by quinocarcin was inhibited by the addition of radical scavengers, superoxide dismutase and catalase suggesting that it is caused by generation of oxygen and/or hydroxyl free radicals. DNA polymerase I from Escherichia coli was blocked by quinocarcin.
TL;DR: The isolation characteriza一 tion and structural elucidation of the antibiotic, indolizomycin are reported.
Abstract: As reported in our separate papers,1・2)we obtained the strain SK2-52 by protoplast fUsion treatment between non-antibiotic-producing mutants of Streptomyces griseus and S.tenjimariensis and this produced a new antibiotic. In this communication the isolation characteriza一 tion and structural elucidation of the antibiotic, indolizomycin are reported. The strain SK2-52 was cultured at 27°Cfbr 37hours on a rotatory shaker (180 rpm)in a 500-mlHask containing l 10ml ofamedium[2.0% dextrin,2.0%glycero1,0.3%yeast extract, LO% Bacto-Soytone(Dif°Co),0.2%(NH4)2SO4 and O.2%CaCO3, pH 7.4]. Vegetative inoculum
TL;DR: The regulation of tylosin biosynthesis in S. fradiae by ammonium ion is discussed in relation to amino acid metabolism and 13C NMR spectroscopic analysis revealed that iso-butyrate was incorporated into protylonolide at the carbons known to originate from propionate and n- butyrate.
Abstract: The production of tylosin by Streptomyces fradiae KA-427 in a defined medium was inhibited by ammonium ions and by inorganic phosphate. The production of protylonolide, an early lactonic intermediate of tylosin biosynthesis with the same carbon skeleton as tylosin aglycone, by a mutant of strain KA-427 was also reduced by these two kinds of ions. In contrast, the bioconversion of protylonolide to tylosin by another mutant was less susceptible to ammonium ions but was sensitive to inorganic phosphate. The addition of protylonolide to a culture of S. fradiae KA-427 increased the tylosin yield, suggesting that aglycone synthesis is limiting under the conditions used. When L-valine, L-leucine, L-isoleucine, L-threonine, or the corresponding 2-keto acid was added to the culture medium, the protylonolide titer increased. The addition of [14C]valine gave rise to [14C]protylonolide. 13C NMR spectroscopic analysis revealed that iso-butyrate, which is a valine metabolite, was incorporated into protylonolide at the carbons known to originate from propionate and n-butyrate. Taking account of these findings, the regulation of tylosin biosynthesis in S. fradiae by ammonium ion is discussed in relation to amino acid metabolism.