Eiji Higashide

Ansamitocin, a group of novel maytansinoid antibiotics with antitumour properties from Nocardia

WE have isolated a new group of ansamycin antibiotics with potent antitumour activity, from a fermentation broth of Nocardia sp. No. C-15003 (N-l) and have named it ansamitocin. Structures of ansamitocin were found to be similar to maytansine and related maytansinoids obtained from plant sources by Kupchan et al.1–4 and Wani et al.5. These comounds have strong antitumour activities, but development of production would be difficult, because plants containing maytansinoids are only harvested in tropical areas and their content in the plants is extremely low. Some attempts have been made to find a maytansinoid-producing microorganism6, but no success has been reported. We report here the microbial production, isolation and structural elucidation of these antibiotics and their antitumour activities against several experimental tumours in mice.

Induction of β-Lactamase in Proteus vulgaris

SUMMARY: Various β-lactam antibiotics, including monocyclic β-lactams, induced the β-lactamase of Proteus vulgaris: when clinical isolates were induced by benzylpenicillin, each strain produced a single β-lactamase but the activity per milligram dry weight differed from strain to strain. The β-lactamases of the P. vulgaris strains were heterogeneous with respect to their isoelectric points, but had almost the same specific activities, substrate specificities and Michaelis constants. The kinetics of β-lactamase formation were investigated in three strains, each with a different β-lactamase activity. Differential rates of enzyme synthesis and peak activity depended on the concentration of inducer. The plots of the reciprocals of the differential rates versus the reciprocals of the inducer concentrations were linear, and the maximum rate of enzyme synthesis and the concentration of the inducer giving half-maximum induction were determined from this double reciprocal plot. The maximum rates of enzyme synthesis were different in the three strains. The kinetic analysis of β-lactamase formation revealed that the β-lactamase activities in a single bacterial species were determined by differences in the rate of enzyme synthesis and not by differences in the properties of the enzyme.

Motile Actinomycetes: Actinosynnema pretiosum subsp. pretiosum sp. nov., subsp. nov., and Actinosynnema pretiosum subsp. auranticum subsp. nov.

Three strains of motile nocardioform actinomycetes were isolated from sedge blades. The characteristics of these isolates led us to assign them to the genus Actinosynnema. Accordingly, we propose the following new taxa of Actinosynnema: Actinosynnema pretiosum subsp. pretiosum sp. nov., subsp. nov., containing type strain C-15003(N-1) (= IFO 13726 = FERM-P 3992 = ATCC 31281) and strain C-14919(N-2001) (= IFO 13723 = FERM-P 3991 = ATCC 31280); and Actinosynnema pretiosum subsp. auranticum subsp. nov., with type strain C-14482(N-1001) (= IFO 13725 = FERM-P 4130 = ATCC 31309).

Isolation of maridomycins and structure of maridomycin II

Das ausStreptomyces hygroscopicus isolierte neue Makrolid Maridomycin II lässt sich mit Säure Mycarcose und Mycaminose spalten. Auf Grund der Oxidation ins Carbomycin sowie der spektroskopischen Daten wurde die Struktur als II erklärt.

Studies on Streptomycetes

Investigation was made on the mycological and antibacterial properties of a strain No. 46408 isolated from a soil sample collected in Shimoueda, Wakayama Prefecture. The strain No. 46408 was compared with similar strains, St. hygroscopicus and St. halstedii, and it was judged to belong to a new species and therefore named Streptomyces atratus nov. sp. Also a strain A-165-Z1, which produces ilamycin, was referred to on its mycological properties and assumed to resemble St. atratus. St. atratus was found to produce new antibiotics, rufomycin A and B, specially active against acid-fast bacteria.

Interconversion of T-2636 antibiotics produced byStreptomyces rochei var.volubilis

Mit angereicherten Enzympräparaten vonStreptomyces rochei var.volbulis sowie einigen Pilzen Hessen sich die Antibiotica T-2636 A (I) und D (III) zu C (II) beziehungsweise F (IV) reversibel desacetylieren. Die Antibiotica (III) und (IV) wurden auch mit dem EnzymS. rochei var.volubilis dehydriert.

Inhibition of Cilia Regeneration of Tetrahymena by Ansamitocins, New Antitumor Antibiotics

Ansamitocins inhibited cilia regeneration of partially deciliated Tetrahymena pyriformis W, and the activity depended on the acyl groups at the C3 position.

Selective Accumulation of Ansamitocins P-2, P-3 and P-4, and Biosynthetic Origins of Their Acyl Moieties

The factors involved in the selective accumulation of ansamitocins P-2, P-3 and P-4 by Actinosynnema pretiosum subsp. pretiosum No. C-15003 (Synonym: Nocardia sp. No. C-15003) were studied. The production of ansamitocin P-2, with a propionyl moiety at the C-3 position of the ansa chain, was stimulated more than 3-fold by the addition of isoleucine, propionate, pro-pionaldehyde and ^-propyl alcohol to the fermentation medium. The production of ansamitocin P-3, with an isobutyryl moiety, was enhanced by the addition of valine, isobutyrate, isobutyraldehyde and isobutyl alcohol, and the proportion of P-3 reached more than 90% of the total ansamitocins produced. The production of P-4, with an isovaleryl moiety, was stimulated by leucine, isovalerate, isovaleraldehyde and isoamyl alcohol. The radioactive compounds, which selectively stimulated the production of each ansamitocin component, were preferentially incorporated into their respective acyl moieties of ansamitocins. Based on these results, we propose th...

Effect of Aspartic Acid Family Amino Acids on Production of Maridomycin III

An attempt was made to increase the production of maridomycin III (MDM III) as the major component among the six components of maridomycin (maridomycin I, II, III, IV, V and VI). Addition to the production medium, of amino acids belonging to the aspartic acid family and its related compounds, such as l-isoleucine, l-threonine, l-methionine, l-homoserine, dl-α-amino-n-butyric acid and α-ketobutyric acid, resulted in a yield of a large amount of MDM III.MDM III was also formed by intact cells from 4″-depropionyl MDM III and the same compounds. From 4″-depropionyl MDM III and l-isoleucine-U-14C (or dl-α-amino-n-butyric acid-3-14C), MDM III-14C was formed, and a large amount of radioactivity was incorporated into MDM III. On deacylation at C-4″ of the MDM III-14C, about 90% of radioactivity of MDM III-14C was observed as propionic acid-14CIn the same way, SF-837-14C was formed from leucomycin A7 and l-isoleucine-U-14C (or dl-α-amino-n-butyric acid-3-14C), and deacylation of the SF-837-14C at C–3 also gave pro...

Ansamitocin-induced Synchrony in Tetrahymena pyriformis

Ansamitocins inhibited cell division in Tetrahymena pyriformis W at low concentrations and caused cells to become more rounded. Exposure to ansamitocins for 5 h or more resulted in a burst of synchronous division at 100 min after removal of the antibiotics with a maximum division index of 70%. A second burst of synchronous division occurred 300 min after removal with a peak division index of 55%. The rounding of the cell shape was restored by the completion of the first division. When RNA or protein synthesis was blocked by chromomycin A3 or cycloheximide, the first division was suppressed. When DNA synthesis was blocked by methotrexate plus uridine, synchronous division still occurred; furthermore, the DNA content of T. pyriformis cells did not increase before the first division. These findings suggests that the first synchronous division requires RNA and protein synthesis but does not require DNA synthesis. Interference by ansamitocins with the fuction of microtubule systems in T. pyriformis is discussed.