Narasin is a new polyether antibiotic produced by a strain of Streptomyces aureofaciens.It is purified by organic solvent extraction and silica gel chromatography. Narasin is active in vitro against gram-positive bacteria, anaerobic bacteria, and fungi and is effective in protecting chickens from coccidial infections.
Carriomycin, a new polyether antibiotic, was isolated from culture broth of Streptomyces hygroscopicus strain T-42082. It is active against Gram-positive bacteria, several fungi, yeasts and mycoplasma. It is also coccidiostatic. The free acid of carriomycin occurs as colorless prisms having the molecular formula C47H80O15 (M.W. 885.15), m.p. 120-122°C and [α] 25D1 -0.5 in methanol. It has no characteristic absorption maxima in the ultraviolet spectrum. The presence of one carboxyl and three methoxy groups was observed from its infrared, PMR and CMR spectra.
Streptomyces cattleya produced a new cyclopentenedione antibiotic, G2201-C [C6H6O4 (I)], which is moderately active in vitro against Gram-positive bacteria, weakly active against Gram-negative bacteria, and inactive against fungi. G2201-C is toxic to mice.
A32390A is an isonitrile-containing derivative of diacyl D-mannitol. The compound is produced in fermentation as the major component of a metabolic complex known as A32390.A32390A inhibits dopamine-β-hydroxylase, reduces heart and adrenal norephinephrine levels, lowers blood pressure in hypertensive rats, and possesses antibiotic activity vs. Gram-positive bacteria and fungi, including Candida albicans. A32390 is produced in submerged culture by a mold, a species of Pyrenochaeta, NRRL-5786. Glucose and sucrose are among the best carbon sources for the biosynthesis of A32390. Mannitol, although a substituent of the A32390A molecule, supports little or no biosynthesis of the compound when employed as the major carbon source for the fermentation. The addition of crotonic acid derivatives, ethanol, or L-histidine to the fermentation medium enhances the level of A32390 produced.
An inhibitor of dopamine-β-hydroxylase, designated A32390A, was isolated from the culture broth of a Pyrenochaeta species. The inhibitor showed antimicrobial activity against fungi and gram-positive bacteria. Spectroscopic analysis and chemical degradation studies indicated that the structure was 1, 6-di-O-(2-isocyano-3-methylcrotonyl)-D-mannitol.
A32390A, an isonitrile-containing derivative of mannitol, represents a new class of antifungal antibiotics. In vitro antifungal activity of A32390A was found against Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum. In vivo antifungal activity of A32390A was demonstrated in mice infected with C. albicans. Accumulative doses of 37.5-600 mg/kg, administered subcutaneously over a 24-hour period, showed significant activity without demonstrating toxicity. A32390A was effective, but not as effective as amphotericin B, in reducing the number of Candida cells isolated from the kidney of infected mice. Urinary excretion of A32390A accounted for only 10 percent of the administered dose. Improved bioavailability of A32390A was accomplished when the antibiotic was combined with polyvinylpyrrolidone (PVP) in a solid dispersion. Administration of A32390A as a 10 percent dispersion in PVP resulted in increased urinary excretion of the drug and reduced the amount of drug required for in vivo activity.
A new antitumor compound named quadrone was isolated from the culture broth of Aspergillus terreus NRRL 11, 156. Quadrone was active against KB cells in vitro, but did not possess antimicrobial activity.
Chemical and photochemical oxidative methods of de-N-methylation of some gentamicins and sisomicins at the 3"-position are described. Selective acetylation of gentamicins and sisomicins at the 1, 3, 2' and 6' and of gentamicin B at the 1, 3, and 6' positions are achieved by treatment of the free bases with carbon dioxide prior to acetylation. De-N-methylation of the above selectively blocked gentamicins and sisomicins followed by re-alkylation at the 3"-position and de-N-protection gives a series of 3"-N-alkyl analogues. The in vitro antibacterialproperties of the new derivatives of gentamicins and sisomicins are given.
13C-NMR studies have confirmed the structures of (8S)-8-hydroxyerythromycins A- and B-6, 9;9, 11-acetal proposed by KROWICKI and ZAMOJSKI2, 3) for the products of the m-chloroperbenzoic acid oxidation of 8, 9-anhydroerythromycins A- and B-6, 9-hemiacetal. The preparations of (8S)-8-methylthiomethoxy- and (8S)-8-methoxyerythromycin B-6, 9;9, 11-acetals are described. The latter are stable in aqueous acetic acid under conditions which convert (8S)-8-hydroxyerythromycin B-6, 9;9, 11-acetalinto (8S)-8-hydroxyerythromycin B. In a paper describing the preparation of the C8-epimeric 8-hydroxyerythromycins B, we reported1) that buffered m-chloroperbenzoic acid oxidation of 8, 9-anhydroerythromycin B-6, 9-hemiacetal (1), followed by catalytic reduction of the resulting N-oxide to the free amine, gave (8S, 9S)-8, 9-anhydroerythromycin B-6, 9-hemiacetal-8, 9-epoxide (2). Our assignment of structure 2 was based on the expected course of olefin epoxidation with peracids and with apparently compatible spectral properties. In addition, the facile conversion of 2 to (8S)-8-hydroxyerythromycin B (3) in aqueous acetic acid was expected for the strained epoxy spiroacetal structure (2).
The biotransformation of lankamycin and congeners darcanolide and 11-acetyllankolide by a blocked mutant of the erythromycin-producing organism Streptomyces erythreus, which cannot synthesize erythromycin without supplementation with erythromycin precursors, was investigated. Darcanolide and 11-acetyllankolide were converted into the corresponding 15-deoxy-15-oxo derivatives. Lankamycin was transformed to 15-deoxy-15-oxolankamycin, 4"-deacetyl-l5-deoxy-15-oxolankamycin and 3'-de-O-methyllankamycin. None of the derivatives possessed high antimicrobial activity.
Trimethoprim and erythromycin were shown to have different overall effects on in vivo polysome metabolism in Escherichia coli. In a rel A+-rel A pair of strains, trimethoprim treatment induces a reduction of polysome level to a variable extent, similarly to aminoacyl-tRNA deprivation of cells, but persisting polysomes remain dynamic structures in a state of continual turnover. In contrast, erythromycin stabilizes polysome level to a high value in either kind of strain, but maintained polysomes appear as "frozen" structures unable to undergo ribosome translocation.
The preparation of the deoxy-analogues of two pseudodisaccharide fragments of neomycin, 5-O-β-D-ribofuranosyl-2, 6-dideoxy-streptamine and 6-deoxyneamine is described. When added to the growth medium of a deoxystreptamine-idiotroph of Streptomyces rimosus forma paromomycinus only the latter was incorporated into antibiotic, suggesting in obligatory order for the assembly of sub-units. 4-O-β-D-Ribofuranosyl-2, 6-dideoxystreptamine was also prepared. When added to the growth medium of a deoxystreptamine-idiotroph of Streptomyces fradiae it was converted into the 6-deoxyneomycins, apparently after hydrolysis to 2, 6-dideoxystreptamine. The structure of the protected derivatives of the ribofuranosyl 2, 6-dideoxystreptamines, potentially useful intermediates for the synthesis of novel antibiotics, was shown by using 13C NMR spectroscopy.
Three semisynthetic cephamycin antibiotics (7α-methoxy-cephalosporins), SKF 73678, SK&F 83088 (CS-1170) and cefoxitin, have been found to possess favorable biological and chemotherapeutic properties. All three cephamycins are active In vitro against strains of Staphylococcus aureus and a variety of gram-negative bacilli. Beta-lactamase producing organisms including indole-producing Proteus spp., Enterobacter spp. and Serratia strains as well as certain anaerobic bacteria were found to be susceptible to these antibiotics. SK & F 73678 showed somewhat better MIC values than cefoxitin against multiple strains of bacteria. Strains of Pseudonionas aeruginosa and group D streptococci are essentially insensitive to these compounds. Their binding to serum proteins is relatively low. In mice, cefoxitin showed the most favorable pharmacokinetics with respect to peak serum level, serum half-life and urinary recovery. These cephamycins protected mice experimentally infected with a variety of bacterial strains. All three compounds are rapidly bacteriolytic to the logarithmically growing Escherichia coli and belatedly so to Staphylococcus strains with complete sterilizing effect. SK&F 73678 and SK&F 83088 showed activity and potency comparable to or better than cefoxitin and thus can be considered candidates for clinical study.