Showing papers in "The Journal of Antibiotics in 1976"
903 citations
TL;DR: In this article, a new compound bestatin was discovered and the discovery and isolation of which are reported in the literature, which is an exopeptidase which can be obtained from rat liver, and it hydrolyses an N-terminal peptide bond containing Nterminal arginine or lysine.
Abstract: papain, chymotrypsin, elastase, acid protease and thermolysin have been found in culture filtrates of actinomycetes. Recently we found that exopeptidases have a strong effect on mammalian cell surfaces compared to endopeptidases°). It is possible that the action of hydrolytic enzymes on cell surfaces is involved in various cellular phenomena. We thought that exopeptidase inhibitors would be useful in the analysis of biological functions. So, we started screening of actinomycetes culture filtrates for activity against aminopeptidase B, and found a new compound bestatin, the discovery and isolation of which are reported herein. As described by Hopsu et a1.10', aminopeptidase B (EC 3.4.11.6) is an exopeptidase which can be obtained from rat liver. It hydrolyses an N-terminal peptide bond containing N-terminal arginine or lysine. In order to obtain quantitative values for antiaminopeptidase B activity, we established the following method. The reaction mixture was
688 citations
373 citations
TL;DR: A new antibiotic, trichostatin, was isolated from the metabolites of strains of Streptomyces hygroscopicus and is active against trichophytons and some fungi.
Abstract: A new antibiotic, trichostatin, was isolated from the metabolites of strains of Streptomyces hygroscopicus. It is active against trichophytons and some fungi. The structure was determined to be a derivative of a primary hydroxamic acid by chemical and spectroscopic evidences.
330 citations
TL;DR: Nocardicin A is a new monocyclic β-lactam antibiotic obtained from the fermentation broth of a strain of actinomycetes that exhibits moderate in vitro antibacterial activity against a broad-spectrum of Gram-negative bacteria including Proteus and Pseudomonas.
Abstract: Nocardicin A is a new monocyclic beta-lactam antibiotic obtained from the fermentation broth of a strain of actinomycetes. The producing organism, strain WS 1571, was identified as Nocardia uniformis subsp. tsuyamanensis ATCC 21806. The antibiotic, obtained as colorless crystals, exhibits moderate in vitro antibacterial activity against a broad-spectrum of Gram-negative bacteria including Proteus and Pseudomonas. It has low toxicity in laboratory animals.
226 citations
141 citations
TL;DR: properties, structure, mechanism of action and biosynthesis, there is a renewed interest in the role that antibiotics play in their ecology of soil and in the life of the microbes that produce them.
Abstract: properties, structure, mechanism of action and biosynthesis. During a relatively short period in the late 1940's and early fifties there was a flush of activity on the question of the role of antibiotics in nature. This interest stemmed in the main from investigators who were seeking to understand the mechanism of microbial antagonisms in soil and its relationship to soil-borne plant diseases. At present there is a renewed interest in the role that antibiotics play in their ecology of soil and in the life of the microbes that produce them. Most soils, whether cultivated, grazed or forested contain large numbers of microbes70). BRIAN') has estimated that one gram of surface soil contains the following populations: Bacteria I to 100 million Fungi 50 thousand to a million Actinomycetes 1 to 10 million Algae 10 thousand to 50 thousand Protozoa 100 thousand to a million Their numbers vary a great deal depending on soil type, depth of the soil, season of the year, rainfall and temperature97.T0). Under extreme conditions, such as in tundra, salt flats, and barren soil due to high or low temperatures, or moisture, the population of the soil is relatively homogeneous and their numbers greatly reduced.
140 citations
TL;DR: Results indicate that bestatin has single free amino, hydroxyl and carboxyl groups, but a-amino-ahydroxy-carboxylic acid.
Abstract: Sir: In the preceding paper'', the isolation and physicochemical properties of bestatin, a new aminopeptidase B inhibitor produced by an actinomycetes, were described. In this communication, we report the structure determination of bestatin which is [(2S, 3R)-3amino-2-hydroxy-4-phenylbutanoyl]-L-leucine. Bestatin is obtained as colorless fine needles, m.p. 233-236°C. The molecular formula was established as C16H24N2O4 (M.W. 308) by elemental analysis and mass spectrometry. Anal. Calcd.: C, 62.32; H, 7.82; N, 9.08; 0, 20.75. Found: C, 61.86; H, 7.79; N, 8.61; 0, 21.06. M+ m/e 308. The ultraviolet absorption spectrum suggested the presence of a phenyl chromophore [A`ma°g nm (s): 248(104), 253(139), 259(172), 265(132) and 268 (shoulder)], and the infrared absorption spectrum suggested the presence of an amide bond (1640 and 1545 cm-1 in KBr disc). Bestatin is an amphoteric compound, that is, it affords crystalline monohydrochloride and crystalline monosodium salts. It gives a positive ninhydrin reaction. Potentiometric titration showed the existence of single amino (pKa 8.1) and carboxyl (pKa 3.1) groups, with a titration equivalent of 310. Bestatin gives a monomethyl ester (M+ m/e 322) upon treatment with methanol-HCI, an N-acetyl derivative (M+ m/e 350) by treatment with acetic anhydride-NaOH, and the diacetyl methyl ester (M+ m/e 406) by treatment of the methyl ester with acetic anhydride in pyridine. These results indicate that bestatin has single free amino, hydroxyl and carboxyl groups. Acid hydrolysis of bestatin with 6 N HCl at 105°C for 16 hours yields two ninhydrin-positive products. They are separated by sulfonic acid resin (Dowex 50W x, 8) column chromatography with linear gradient elution between 0.2 M pyridine acetate buffer at pH 3.0 and 1.0 M pyridine acetate buffer at pH 4.75. The fast eluted substance is identical with L-leucine, [a]2 +12.9° (c 0.778, 1 N HCI). The late eluted substance (I) is a new amino acid. This amino acid is obtained as colorless needles from water, m.p. 219-221°C, [a]p°+ 27.9° (c 0.717, 1 N HC1). It has the molecular formula C1OH13NO3 (M.W. 195). Anal. Calcd.: C, 61.53; H, 6.71; N, 7.17; 0, 24.59. Found: C, 61.23; H, 6.60; N, 7.04; 0, 24.50. Potentiometric titration indicates the presence of single amino (pKa 8.6) and carboxyl (pKa 2.5) groups with a titration equivalent of 212. The pKa value of the carboxyl function suggests that I is not an a-amino~-hydroxy-carboxylic acid, but a-amino-ahydroxy-carboxylic acid. The PMR spectrum of I-hydrochloride in deuteromethanol indicates the presence of a phenyl group (5 protons centered at 67.30) and a carbon chain: -CH2-CH-CH[2 protons at 5 3 .06
139 citations
TL;DR: Structural modification of the antibiotic pleuromutilin has afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and has permitted conclusions to be reached about structure-activity relationships.
Abstract: Structural modification of the antibiotic pleuromutilin has afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and has permitted conclusions to be reached about structure-activity relationships. The carbonyl group in the five-membered ring and the hydroxyl group at C11 seem to be essential for activity. The vinyl group can be hydrogenated without loss of activity. Chemical modification at C14 offers the most possibilities for achieving the best activity and solubility properties. Mutilin, and other compounds with a free OH at C14, are inactive. It was shown that mutilin esters of substituted thioglycolic acids had distinctly superior MIC values, especially in combination with a tertiary amino group in the side chain, the latter group of derivatives having MIC values better than pleuromutilin by a factor of more than 10. Further variation within this group led to the development of 14-deoxy-14-[(2-diethylaminoethyl) thioacetoxy]-mutilin hydrogen fumarate (81.723 hfu, tiamulin) for extensive investigation of its chemotherapeutic potential.
118 citations
Journal Article•
TL;DR: Aplasmomycin this article is a new antibiotic, which inhibits growth of Gram-positive bacteria including myobacteria in vitro, and plasmodia in vivo, obtained from a strain of Streptomyces griseus isolated from shallow sea sediment in Sagami Bay.
Abstract: A new antibiotic, aplasmomycin, which inhibits growth of Gram-positive bacteria including myobacteria in vitro, and plasmodia in vivo was obtained from a strain of Streptomyces griseus isolated from shallow sea sediment in Sagami Bay. The antibiotic forms colorless needle-like crystals and has a molecular formula of C41H60O14Na. Based on its physical and chemical properties, aplasmomycin was concluded to be a new antibiotic. The antibiotic was produced in selected media devised to relate to a marine environment.
115 citations
TL;DR: A new antibiotic, aplasmomycin, which inhibits growth of Gram-positive bacteria including myobacteria in vitro, and plasmodia in vivo was obtained from a strain of Streptomyces griseus isolated from shallow sea sediment in Sagami Bay.
Abstract: A new antibiotic, aplasmomycin, which inhibits growth of Gram-positive bacteria including myobacteria in vitro, and plasmodia in vivo was obtained from a strain of Streptomyces griseus isolated from shallow sea sediment in Sagami Bay. The antibiotic forms colorless needle-like crystals and has a molecular formula of C41H60O14Na. Based on its physical and chemical properties, aplasmomycin was concluded to be a new antibiotic. The antibiotic was produced in selected media devised to relate to a marine environment.
TL;DR: In inhibition by citrinin of cholesterol and ergosterol synthesis and its hypocholesterolemic activity in rats, the inhibition of endogenous cholesterol synthesis could lead to a lowering of its level in the plasma.
Abstract: A compound active against sterol biosynthesis was isolated from the culture filtrate of the fungus Prthium ultimum IAM 6073 and identified as citrinin which had been isolated as an antibiotic.') The sequence of reactions by which cholesterol is formed from acetyl-CoA is one of the most complex biosynthetic pathways in eukaryotic cells. In every vertebrate species so far studied, potent activity in cholesterol synthesis can be detected in the liver which seems to be the sole organ supplying plasma cholesterol. Because of the importance of the plasma cholesterol level in atherosclerosis, several approaches have been made to control it by decreasing cholesterol synthesis in the liver.2~4) The inhibition of endogenous cholesterol synthesis could lead to a lowering of its level in the plasma. This communication describes inhibition by citrinin of cholesterol and ergosterol synthesis and its hypocholesterolemic activity in rats. The enzymatic synthesis of cholesterol was assayed by measuring the radioactive nonsaponifiable products derived from 14C-acetate in a rat liver enzyme system by the method of KNAUSS et al.5) Culture filtrates of microorganisms including fungi, bacteria, and actinomycetes were tested for inhibitory activity in this assay system, and Pvthium ultimum was selected as one of the producers of an inhibitor. The fungus was cultured aerobically in a medium containing 2.0% glucose, 2% peptone and 0.3 % corn steep liquor in a 30-liter fermentor for 4 days. The culture filtrate was adjusted to pH 2, and the active compound was extracted with benzene. The extract was concentrated in vacuo, resulting in the formation of yellowish crystals of the active compound. The compound was recrystallized from hot chloroform. Calcd.: C 62.39, H 5.64, O 31.97 Found: C 62.39, H 5.58, O 32.03 The chemical structure of 4,6-dihydro-8-hydroxy-3,4, 5-trimethyl 6 oxo3 H-2-benzopyran-7 carboxylic acid was suggested by n.m.r. spectrum. The identity with citrinin was proven by comparison with authentic samples (kindly supplied by Dr. S. UDAGAWA, National Institute of Hygienic Science, Tokyo). As shown in Fig. 1, citrinin strongly inhibited cholesterol synthesis from 14C-acetate. The concentration at which cholesterol synthesis was inhibited by 50 % was about 8.5 mcg/ml (3.4 x 10-5M). Under the same conditions, 14C-acetate incorporation into fatty acid fraction was also reduced by citrinin but to a lesser extent. The concentration of the inhibitor required for 50 inhibition of fatty acid synthesis was approximately 50 mcg/ml. Citrinin was also inhibitory in the sterol synthesizing system of the yeast Saccharomyces cerevisiae in which 14C-acetate incorporation into nonsaponifiable lipids was determined as described by KAWAGUCHI (Fig. 1).e) At a concentration of 100 mcg/ml, the inhibitor reduced the sterol synthesis by approximately 50%. For studies of hypocholesterolemic effect of
TL;DR: The history of the aminocyclitol antibiotics dates from the discovery in 1943 of streptomycin by Waksman’s group at Rutgers to the discovery of neomycin, parommycin, kanamycin, gentamicin, sisomicin, butirosin, ribostamycin and hygromycin.
Abstract: The history of the aminocyclitol antibiotics dates from the discovery in 1943 of streptomycin by Waksman’s group at Rutgers (Schatz et al., 1946). This was followed by the discovery of neomycin, paromomycin, kanamycin, gentamicin, sisomicin, butirosin, ribostamycin, spectinomycin, fortimicin, validamycin, minosaminomycin, and hygromycin, to name but some of the naturally occurring members of this class of compounds.
TL;DR: Cefuroxime is a new broad spectrum cephalosporin antibiotic for administration by injection that produced high, long-lasting blood levels with virtually complete recovery of unchanged antibiotic in the urine.
Abstract: Cefuroxime is a new broad spectrum cephalosporin antibiotic for administration by injection. It is stable to most beta-lactamases. It is active against gram-positive organisms, including penicillinase-producing staphylococci, and has wide activity against gram-negative bacilli including Enterobacter and many strains of indole-positive Proteus spp. The substance is also highly active against Haemophilus influenzae and Neisseria gonorrhoeae. Studies on human volunteers showed that it produced high, long-lasting blood levels with virtually complete recovery of unchanged antibiotic in the urine. No evidence of toxicity due to cefuroxime was found. Slight, short-lived pain followed intramuscular injection, and the compound was well tolerated intravenously.
TL;DR: Iturin A, an antifungal lipopeptide characterized by the presence of homologous liposoluble beta-aminoacids was found to be the active component to bacillomycin B, bacillsomycin R and eumycin.
Abstract: Iturin A, an antifungal lipopeptide characterized by the presence of homologous liposoluble beta-aminoacids was found to be the active component to bacillomycin B, bacillomycin R and eumycin. Iturin A was identified by thin-layer chromatography, aminoacid analysis and by characterization of liposoluble aminoacids and peptides. Another two preparations: the antibiotic of Raubitschek and the bacillomycin of Landy et al. contain components of the same structural type but they are different from iturin A.
TL;DR: A series of new derivatives of the antibiotic pleuromutilin, produced by some Basidiomycetes, was synthesized by chemical modification of natural pleurumutilin and contain basic functional groups in the side chain at C14 of the mutilin skeleton.
Abstract: A series of new derivatives of the antibiotic pleuromutilin, produced by some Basidiomycetes, was synthesized by chemical modification of natural pleuromutilin. Most of them contain basic functional groups in the side chain at C14 of the mutilin skeleton. The monotosylate of pleuromutilin was used as a versatile intermediate for displacement by N-, O- and S-nucleophiles.
TL;DR: Three strains of Pseudomonas aeruginosa resistant to Gentamicin obtained as representative gentamicin-resistant clinical isolates from the University of Alberta Hospital (UAH) in Edmonton, Canada were characterized to determine their mechanism of resistance.
Abstract: Three strains of Pseudomonas aeruginosa resistant to gentamicin obtained as representative gentamicin-resistant clinical isolates from the University of Alberta Hospital (UAH) in Edmonton, Canada were characterized to determine their mechanism of resistance. All strains showed wide aminoglycoside resistance (tobramycin, sisomicin, amikacin, streptomycin, kanamycin, SCH 20569) but contained no evidence of gentamicin-acetylating, adenylating or phosphorylating activity. Gentamicin inhibited amino-acid incorporation in cell-free systems equally well with either ribosomes or soluble cell fractions obtained from either resistant or sensitive strains. Plasmid DNA was detected in two strains but resistance could not be transferred by conjugation to either P. aeruginosa or Escherichia coli recipients. The resistant strains showed a marked reduction in energy-dependent accumulation of gentamicin compared to a sensitive strain. These strains which are common at UAH are most likely resistant due to a failure of gentamicin to be transported across the cytoplasmic membrane to ribosomal sites until relatively high external gentamicin concentrations.
TL;DR: The properties of number of kalafungin derivatives and analogues are consistent with the proposed structure and the absolute stereochemistry of the three active centers was determined to be RRR by optical rotatory dispersion comparisons.
Abstract: The properties of number of kalafungin derivatives and analogues are consistent with the proposed structure. The absolute stereochemistry of the three active centers was determined to be RRR by optical rotatory dispersion comparisons.
TL;DR: The structures of nocardicins A and B, novel monocyclic beta-lactam antibiotics produced by a strain of Nocardia, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence.
Abstract: The structures of nocardicins A and B, novel monocyclic β-lactam antibiotics produced by a strain of Nocardia, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence. They are the first examples of monocyclic β-lactam antibiotics possessing relatively high antimicrobial activity, and are stereochemically and biologically related to penicillins and cephalosporins.
TL;DR: Herbicidins A and B, two new antibiotics with selective and contact herbicidal activity, were produced by a new species of Streptomyces designated as S. sagononensis and indicated some activity against fungi in vitro and Xanthomonas oryzae in vivo.
Abstract: Herbicidins A and B, two new antibiotics with selective and contact herbicidal activity, were produced by a new species of Streptomyces designated as S. sagononensis. Among tested microorganisms, herbicidins indicated some activity against fungi in vitro and Xanthomonas oryzae in vivo. Their characteristic features were brought into relief by their selective and contact killing effect on many dicotyledonous plant as well as their inhibition of germination of the plant seeds, such as Chinese cabbage.
TL;DR: In this article, a microbonded propylamine silica with a solvent system containing acetic acid, methanol, acetonitrile and water was used for the isolation of cephalosporin C directly from the filtered broth of C. acremonium fermentation.
Abstract: Microbonded propylamine silica with a solvent system containing acetic acid, methanol, acetonitrile and water (2:4:7.5:86.5) is suitable for an efficient separation of mixtures containing several closely related cephem derivatives. The same system with preparative columns was used for the isolation of cephalosporin C directly from the filtered broth of C. acremonium fermentation.
TL;DR: Enterocin is a new antibiotic isolated from cultures of two strains of StrePTomyces, which were given the names Streptomyces candidus var.
Abstract: Enterocin is a new antibiotic isolated from cultures of two strains of Streptomyces, which were given the names Streptomyces candidus var. enterostaticus WS-8096 and variant M-127 of Streptomyces viridochromogenes. Its elementary analysis and mass spectroscopic measurement suggest the molecular formula is C22H20010. The ultraviolet absorption gave two maximal peaks at 250 nm and 283 nm in methanol. Enterocin has static activities against gram-positive and gram-negative bacteria and no activity against fungi and yeast.
TL;DR: A new variety of Streptomyces hygroscopicus was isolated from a Kalamazoo soil and identified as var.
Abstract: A new variety of Streptomyces hygroscopicus was isolated from a Kalamazoo soil. This isolate is described and identified as var. geldanus. When fermented in preferential media it produces geldanamycin, nigericin, nocardamine, and a libanamycin-like activity. Fermentation conditions, chromatographic separation, and antimicrobial spectra of the antibiotics are given.
TL;DR: Physico-chemical characterization revealed that herbicidins are new antibiotics having an adenine nucleoside moiety in their structures.
Abstract: Herbicidins were produced in submerged fermentation by Streptomyces saganonensis. Isolation of the antibiotics from the culture broth was performed by adsorption on resinous adsorbent followed by elution with aqueous acetone. Herbicidins A and B were separated from each other by counter-current distribution on a Ronor column or by silica gel chromatography. Physico-chemical characterization revealed that herbicidins are new antibiotics having an adenine nucleoside moiety in their structures.
TL;DR: Carbon magnetic resonance has been used to show conclusively that six polyene macrolide antibiotics containing keto groups (the heptaene amphotericin B, tetraene-diene nystatin A1, and the tetraenes tetrin A, tetrin B, pimaricin, and lucensomycin) exist in the hemiketal form in solution as discussed by the authors.
Abstract: Carbon magnetic resonance establishes conclusively that six polyene macrolide antibiotics containing keto groups (the heptaene amphotericin B, the tetraene-diene nystatin A1, and the tetraenes tetrin A, tetrin B, pimaricin, and lucensomycin) exist in the hemiketal form in solution. Their spectra all contain a hemiketal carbon's absorption near 97 ppm but lack a keto carbon's absorption near 210 ppm. The non-polyenic macrolide erythromycin, on the other hand, exists in the keto form.
TL;DR: AHPAJ, an acid hydrolysis product of bestatin, is a new naturally-occuring amino acid, and (2S, 3R)-AHPA was separated from its diastereoisomer by Dowex 50 chromatography using linear gradient elution between 0.36m pyridineacetate (pH 3.52) and 0.48 M p Pyridine-acetate(pH3.80) buffer.
Abstract: Sir: Bestatin is a specific inhibitor of aminopeptidase B and leucine aminopeptidase.l) It was isolated from a culture filtrate of Streptomyces olivoreticuli. Its structure was elucidated as [(2S,3 R)-3-amino-2-hydroxy -4phenylbutanoyl] L-leucine.2.3> (2S,3R)-3-Amino-2-hydroxy-4phenylbutanoic acid [abbreviated as (2S,3R)AHPAJ, an acid hydrolysis product of bestatin, is a new naturally-occuring amino acid. In this communication, the chemical synthesis of bestatin by the scheme shown in Fig. 1, is reported. To an ethyl acetate solution of benzyloxycarbonyl-D-phenylalanine kept at 0°C was added one equivalent of dicyclohexylcarbodiimide (DCC). Thirty minutes after addition, one equivalent of pyrazole was added. The reaction mixture was stirred for 16 hours at 0°C. After removal of resulting dicyclohexylurea by filtration, the filtrate was evaporated under reduced pressure to yield crude pyrazolide of benzyloxycarbonyl-D-phenylalanine (1). It was crystallized from ethyl acetate, mp 108-109°C (83//0 yield). To a tetrahydrofuran (THF) solution of 1 kept at -15--20'C was added 2 eq. of LiAIH4 in THE intermittently over a period of 30 minutes. The reaction mixture was stirred for 30 minutes at the same temperature. After decomposition of the excess reagent by addition of 2 N HCI, the solvent was evaporated and the residue was extracted with ethyl acetate. The extract was washed with water and then dried. The dried material, benzyloxycarbonyl D phenylalaninal (2), was used in the following reaction without further purification. An aqueous suspension of 2 was treated with 2 eq. of NaHSO; at 60°C for 2 hours to form the adduct (3). It was extracted from the clear reaction mixture with ethyl acetate and crystalline powder of 3 was obtained after evaporation of the solvent in 74° yield starting from the pyrazolide. To an ice-cold aqueous solution of 3 was added I eq. of NaCN over a period of l hour to form the cyanohydrin (4). It was extracted with ethyl acetate in 94'/0 yield. Refiux of 4 in 6 N HCI gave AHPA in 79 yield. As expected, AHPA thus obtained was a mixture of (2S,3R)and (2R,3R)-isomers. (2S, 3R)-AHPA was separated from its diastereoisomer by Dowex 50 chromatography using linear gradient elution between 0.36m pyridineacetate (pH 3.52) and 0.48 M pyridine-acetate (pH 3.80) buffer. (2S,3R)-AHPA was eluted later than the diastereoisomer. The synthetic (2S,3R)-AHPA was identical with natural material, [a]n'+27.7° (c 1.0, 1 N HCI) [Lit.°1 [a] 27.9° (c 0.717, 1 N HC])]. On a cellulose thinlayer chromatogram using butanol saturated with