A taxonomic study of strain B-98891, which produced an antibiotic effective against powdery mildew of barley, identified it as Streptoverticillium rimofaciens. On agar media the antibiotic, which was named mildiomycin, was only weakly active against most fungi and bacteria tested. However, it inhibited some Mycobacterium and Rhodotorula, and it showed excellent control of powdery mildew of barley plants in greenhouse tests at concentrations between 31.2 and 62.5 ppm. Rhodotorula rubra IFO 0907 was selected as the test organism for in vitro assay of mildiomycin.

View full abstract

A new antibiotic mildiomycin, strongly active against powdery mildew, was isolated from the culture filtrate of Streptoverticillium rimofaciens B-98891. It is a water-soluble basic antibiotic and was purified by ion-exchange and adsorption chromatography. The molecular formula of the purified compound was determined to be C₁₉H₃₀N₈O₉(H₂O) from physical and chemical data. The UV and NMR spectra suggested that this antibiotic is a nucleoside. On acidic hydrolysis it gave 5-hydroxymethyl cytosine which has not previously been found in
nucleoside antibiotics.

View full abstract

A new polyene class antibiotic, aurantinin (KM-214), was isolated from the fermentation broth of Bacillus aurantinus MASUMA and OMURA sp. nov. The substance is a conjugated triene with a molecular weight of 618 and molecular formula C₃₅H₅₄O₉, and melts at 139-
140°C. The antibiotic is active in vitro against Gram-positive bacteria, but not against yeast and fungi.

View full abstract

Structure elucidation and some biological properties of an antiviral and antifungal antibiotic, funiculosin, are summarized. Funiculosin is a derivative of N-methyl-4-hydroxy-3, 5- disubstituted-2-pyridone containing a novel substituent, cyclopentanetetrol moiety, that is reported here for the first time in a natural product. The antibiotic protects guinea pigs efficiently against experimental trichophytosis. Toxicity of funiculosin is unique and highly selective for animal species.

View full abstract

The activity of rapamycin, a new anti-Candida antibiotic, was not affected by pH values between 6 and 8; at pH 4, however, activity was abolished. The MIC of rapamycin did not vary drastically with the size of inoculum: a ten-fold dilution of the inoculum reduced the MIC only two-fold. Serum binding was extensive. Serum levels obtained in mice were higher on subcutaneous injection than with oral administration. Dogs absorbed rapamycin after oral administration. Rapamycin cured systemic candidosis in mice: PD₅₀ s. c. was 9.5 mg/kg; PD₅₀ p. o. was 11 mg/kg. In the same experimental infections amphotericin B and nystatin exhibited PD₅₀ values of <0.25 mg and >4, 000 units/kg respectively. Rapamycin and amphotericin B, administered at 1, 4 and 24 hours after infection, gave approximately the same percent survival after 30 days of observation. When the above treatment was extended by an additional daily treatment for 6 days, rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period. Vaginal candidosis in female rats was treated efficiently (91% cure) by rapamycin administered orally. No increase of resistance of C. albicans was observed during treatment.

View full abstract

The synthesis and in vitro structure-activity relationship of 7-ureidoacetyl cephalosporins carrying various substituents in the 3-position, compounds that showed an enhanced broad spectrum of antibacterial activity, has been outlined. Contrary to most of the previous observations with diastereomeric isomers of cephalosporins, it has been found that the L-side chain isomers also are very potent antibiotics and are even more active inhibitors of certain β-lactamase- producing Gram-negative bacteria than the corresponding D-side chain isomers. SQ 69, 613, 7β- [[L-[(aminocarbonyl)amino]-2-furanylacetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt, the most active compound tested, except for activity against staphylococci, was as active in vitro as cefamandole.

View full abstract

The synthesis and antibacterial activity in vitro of 7-methoxylated cephalosporins having a thienylureidoacetyl or a thienylglycyl C-7 side-chain are described. Acylation of 7β-amino-7- methoxycephems with a novel 2-aminooxazolone hydrochloride under neutral conditions gave the thienylureidoacetyl derivatives in good yield with retention of configuration. 7β-[[D-[(Aminocarbonyl)amino]-2-thienylacetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylica cid sodium salt (SQ 14, 359) was found to have a broad-spectrum of antibacterial activity in vitro, particularly against β-lactamase-producing organisms.

View full abstract

A series of 7β-ureidoacetyl, 7α-H and 7α-OCH₃ cephalosporin antibiotics have shown broad-spectrum antibacterial activity in vitro. In the 7α-H but not in the 7α-OCH₃ series, contrary to experience in the antibiotic field, the L-isomers were substantially more active than the D-isomers both in vitro and in vivo particularly, but not exclusively, against Enterobacteriaceae that produce potent chromosomal cephalosporinases. Enhanced resistance to and inhibition of β-lactamase(s) appeared to be responsible for this effect. Studies in vitro specifically with 7β-thienylureidoacetyl derivatives showed that D-isomers interacted with L-isomers in the 7α-OCH₃ series in a synergistic manner against "cephalosporinase-type" enzyme producers while isomers in the 7α-H series did not. Examples were presented in which this favorable event resulted in improved efficacy of the racemic mixture over the pure D- or L-isomer alone in appropriate experimental infections.

View full abstract

Cephalosporins are chemotherapeutic agents whose spectrum and use are limited to antibacterial activity. Therefore, it was of interest to find several new semisynthetic cephalosporins which possess in vitro antifungal activity against Trichophyton mentagrophytes, Candida albicans and certain other yeasts. Five new cephalosporins containing the 2-pyridinethiol 1- oxide grouping were examined. Four with this heterocyclic moiety in the 3-position were found to have activity. One with the grouping in the 7-acyl-side chain was inactive. The degree of the antifungal activity was influenced by the substituent at the 7-position. The cephalosporin with a p-hydroxyphenylglycyl side chain was the most potent against the fungal strains studied. Despite this in vitro antifungal activity, none of the compounds protected mice against a systemic Candida albicans infection. All of these cephalosporins had broad spectrum in vitro and in vivo antibacterial activity.

View full abstract

The biosynthesis of clavulanic acid was investigated by feeding ¹³C-labelled precursors to Streptomyces clavuligerus fermentations. The resulting samples of clavulanic acid were isolated as the benzyl ester and were examined by ¹³C NMR spectroscopy for ¹³C-enrichment. The results showed that the carbon skeleton of 1, 3-¹³C₂-glycerol was incorporated intact into the three β-lactam carbons of clavulanic acid. Studies with 1-¹³C-acetate, 2-¹³C-acetate and 1, 2-¹³C₂-acetate indicated that the remaining five carbons of clavulanic acid were probably derived from α-ketoglutarate. 1-¹³C-Propionate and 3-¹³C-propionate were not metabolised via the same route as glycerol, but were probably converted to succinate, via methylmalonyl CoA, and hence via the tricarboxylic acid cycle to the clavulanic acid precursors.

View full abstract

A single dose of 20 mg/kg of cefsulodin [3-(4-carbamoyl-1-pyridiniomethyl)-7β-(D-α-sulfophenylacetamido)- ceph-3-em-4-carboxylate monosodium salt] was administered subcutaneously to mice, and intramuscularly to rats and dogs. The plasma and tissue levels reached the peak 15-30 minutes after administration. In mice and rats, no plasma levels were measurable 2 and 4 hours after administration. In dogs, the plasma levels were measurable 6 hours after administration. The level in the kidney of mice was slightly lower than the plasma level, while in rats and dogs, the level in the kidney was higher than the plasma level. The cefsulodin levels in the lung of rats and dogs were relatively high, and the level in mice was relatively low. The hepatic levels were very low in all test animal species. Cefsulodin was mainly excreted into the urine, and the excretion of cefsulodin into the bile was very slight.

View full abstract

A large number of compounds including actinobolin, adrenochrome, amicetin, anisomycin, aurintricarboxylic acid, blasticidin S, chartreusin, chlortetracycline, cycloheximide, doxycycline, edeine A₁, edeine complex, emetine, fusidic acid, gougerotin, GppCH₂p, oxytetracycline, pactamycin, polydextran sulphate, puromycin, pyrocatechol violet, sparsomycin and tubulosine have been tested for inhibitory effects on protein synthesis in cultured cells from both mouse fibroblasts (3T6 cells) and chick embryo fibroblasts (CEF). Essentially, similar results were obtained with both cell types with the most effective inhibitors being pactamycin, emetine, tubulosine, anisomycin and cycloheximide and with no significant inhibitory activity being detected with edeine complex, edeine A₁, GppCH₂p, polydextran sulphate, aurintricarboxylic acid, pyrocatechol violet and adrenochrome. The concentration of pactamycin required to produce 50%. inhibition of protein synthesis approximated 5×10^-9M, but for most of the inhibitors it ranged from 5×10^-6 M to 5×10^-4 M. The molecular basis underlying these differences may be related, in addition to their intrinsic inhibitory power, to differences in permeability of the cells towards the various drugs tested. Alternatively, active accumulation of the drugs by the cells may be the variable parameter.

View full abstract

The effects of polymyxin B (PB) on outer membrane (OM) components from resistant (strain 08) and sensitive (strain Bizio) cells of Serratia marcescens were characterized by chemical analysis and polyacrylamide gel electrophoresis (PGE) in sodium dodecylsulfate. Chemical analysis revealed no major differences in the OM fractions after PB treatment of both strains, except for the loss of protein in PB treated OM of the sensitive strain. The yield and composition between the lipopolysaccharides (LPS) of the two strains were different both before and after treatment. PGE revealed that there was a complex formation between the LPS of resistant strain and PB but both dissociation and degradation occurred in the LPS components in the sensitive strain. In addition, it was found that the protein components were destabilized by PB with subsequent loss of some of the components from OM of the sensitive strain. The difference in the amount of LPS and their ability to complex with PB may reflect different degrees of antibiotic susceptibility of these two strains of S. marcescens. A sequential multistep mechanism is proposed for the action of PB on outer membranes of this species.

View full abstract

The effect of demycarosylturimycin H on bacterial growth, polypeptide synthesis and peptidyltransferase was studied. The effects are compared with those of intact turimycins acylated or deacylated in 4''-position of mycarose. The removal of the acyl group in 4''- position of mycarose leads to a total loss of inhibition of acceptor substrate binding while the removal of acyl mycarose moiety changes the pattern of inhibition of polypeptide synthesis.

View full abstract

Four cytotoxic antibiotics, bikaverin, duclauxine, PSX-1 and vermiculine, were examined with respect to their interference with glycolysis and respiration and their possible ionophoric or cytolytic activity. Duclauxine was found to be an inhibitor of respiration and bikaverin an uncoupler of oxidative phosphorylation of tumor cells and of isolated rat liver mitochondria. Bikaverin was also found to be an efficient haemolytic agent. Vermiculine and PSX-1 showed no effect in the systems employed.

View full abstract