Merulidial, a new antibiotic, was isolated from the culture fluid of the Basidiomycete Merulius tremellosus FR., strain No. WQ 568. Merulidial inhibits a variety of bacteria and fungi. In cells of the ascitic form of EHRLICH carcinoma, DNA synthesis is inhibited at lower concentration as compared to RNA and protein synthesis. Merulidial shows mutagenicity when incubated with the his--mutant TA 100 for Salmonella typhimurium (B.N. AMES). The molecular formula as determined by high resolution mass spectrometry is C15H20O3.
The cation selectivity profiles of the carboxylic ionophores, carriomycin, lonomycin and etheromycin, have been investigated by measuring the complexation affinities for metal cations and the cation transport activity through an organic barrier. In a two-phase partition study, carriomycin and lonomycin formed complexes more readily with K+ than with NH4+, Rb+ or Na+, but not with Li+ or Cs+. On the other hand, etheromycin exhibited a great preference for K+ or NH4+ over Na+, Li+ or Rb+, but displayed no binding affinity for Cs+. The alkaline degradation product of lonomycin exhibited a preference for K+ or Na+, but its complexation affinities were much lower than those of the parent compound. Carriomycin, lonomycin and etheromycin efficiently transported K+, Rb+ and Na+ through a CC14 barrier. But did not carry Ca2+. These antibiotics caused a massive release of K+, Rb+ or Na+, but not of Li+ and Cs+, from mitochondria previously loaded with these cations by valinomycin or monazomycin. Thus, it is concluded that carriomycin, lonomycin and etheromycin are monovalent cation selective ionophores.
The susceptibility of more than 40 strains of Gram-negative and Gram-positive anaerobes to tiamulin (Sandoz 81.723 hfu), a new pleuromulin (pleuromutilin) derivative, was determined by broth dilution and agar dilution tests. The influence of density of the inoculum upon MICs was studied by a specially designed pour plate-technique. Bacteroides fragilis, B. vulgatus, B. splanchnicus, B. oralis, B. asaccharolyticus, B. inelaninogenicus, Fusobacterium fusiforme (F. nucleatum), Sphaerophorus necrophorus, Clostridium perfringens, C. fallax, Propionibacterium aches and several species of Peptococcaceae showed broth dilution MICs of 0.03-11μg/ml. Members of B. thetaiotaomicron, B. distasonis and S. freundii (F. mortiferum) were inhibited by 8-32μg/ml and 2 strains of S. varies had a broth dilution MIC of 256μg/ml. With most strains, the agar dilution MICs were 2-4-8 times the broth dilution MICs. In pour platetests, the MICs were not considerably influenced by varying initial concentrations of viable cells. With most anaerobes, the MBCs of tiamulin were more than 100-fold higher than the MICs. The results obtained indicated that, apart from S. varies, B. thetaiotaomicron, B. distasonis and S. freundii (F. mortiferum), members of 16 other anaerobic species including B. fragilis were without exception sensitive to tiamulin.
Neothramycin was observed to prevent growth of mouse lymphoblastoma L5178Y and HeLa cells at the concentration of 0.5-1.0μg/ml and exhibited a lethal effect at 5.0μg/ml. Approximately 50% growth inhibition of E. coli was found at the concentration of 37 μg/ml. The effect of neothramycin on macromolecular syntheses in the mammalian and bacterial cells was investigated. The antibiotic produced a preferential inhibition of RNA over DNA synthesis in the intact cells of lymphoblastoma L5178Y: i.e. approximately 50% inhibition of the former was observed at the antibiotic concentration of 1.4 μg/ml, and that of the latter at 12.0μg/ml. Protein synthesis was not significantly affected. Contrary to the effect in the mammalian cells, thymine uptake into DNA was more markedly blocked than uridine incorporation into RNA by the antibiotic in the intact cells of E. coli. However, neothramycin was observed to cause a significant degradation of DNA, and the apparent inhibition of thymine uptake seemed to be due to degradation of DNA but not to the inhibition of net DNA synthesis. In E. coli the antibiotic prevented RNA synthesis more profoundly than DNA synthesis as in the mammalian cells. DNA synthesis with toluene-treated cells of E. coli polA- was not significantly affected by neothramycin, while RNA synthesis with the same system was markedly blocked by the antibiotic. Neothramycin was demonstrated to prevent DNA-dependent RNA and DNA polymerase reactions, using E. coli enzymes and calf thymus DNA as a template. RNA polymerase reaction was more profoundly inhibited than DNA polymerase I: i.e. approximately 50% inhibition of RNA polymerase reaction was observed at the antibiotic concentration of 11 μg/ml, and that of DNA polymerase I at 100 μg/ml. The inhibition degree of DNA polymerase I was reversed by the increasing concentration of template DNA but not by that of the enzyme, suggesting the direct interaction of the antibiotic with DNA. The degree of inhibition of the polymerase reactions depended upon the period of preincubation of template DNA and neothramycin, increasing gradually until the preincubation reached 60 minutes. It suggested that the interaction of DNA and the antibiotic might need a certain time.
A rapid and accurate high speed liquid chromatographic method has been developed for the determination of cephalexin in human plasma and urine. The method involves micropore filtration of urine specimens and methanol extraction of plasma samples followed by HSLC separation on a bonded reverse phase column utilizing a mobile phase of methanol-water containing acetic acid. The quantitativity of UV response at 254 nm covered a wide range of cephalexin concentrations down to 0.5 μg/ml, and no metabolite peaks were detected. The time courses of plasma level and urinary excretion were determined until 6 hours after oral administration of cephalexin capsules to healthy volunteers. The pharmacokinetic parameters were estimated using a two compartment open model.
Alkalimetric pH-stat titrations of cephalosporin C, cephacetril and their deacetyl derivatives using an acetyl esterase and β-lactamase are described. The esterase was used to assay highly purified samples of cephalosporin C and cephacetril, and also to prepare analytically defined solutions of the deacetyl cephalosporins. actamase-catalyzed hydrolysis of the parent compounds was then found to generate exactly 2 equivalents of acid per mole; that of the deacetyl derivatives exactly 1 equivalent.
The hydrolysis of several phenylacetylamino compounds was studied using a purified preparation of E. coli penicillin acylase. The L-isomers of phenylacetyl amino acids were cleaved much faster than the D-isomers. The same observation was made for some phenylacetylamino β-lactams. When the β-lactam ring is incorporated in a penam or cephem ring system, the D-isomers were hydrolysed somewhat faster than the L-isomers. We also confirmed that benzylpenicillins with an hydroxy- or an amino-group in α-position of the side chain were hydrolysed, both in the normal and the 6-epi-series.