A new phenazine antibiotic, DOB-41, was isolated from the culture broth of a Pseudomonas strain. The antibiotic obtained as yellow crystals showed UV maxima at 255 nm and 370 nm. A molecular formula, C₁₉H₁₈N₂O₆, was indicated by elemental analysis and mass spectrometry. The structure was elucidated by X-ray diffraction analysis. The antibiotic exhibited inhibitory activity against Gram-positive bacteria, and antitumor effect against leukemia P388 in mice.

View full abstract

Pyridazomycin (1), a new antifungal antibiotic produced by Streptomyces violaceoniger sp. griseofuscus (strain Tü 2557), was detected in a selective screening against Mucor hiemalis (Tü 179/180). The amino acid side chain of 1 can be seen as L-ornithine, whose γ-nitrogen atom is part of a pyridazine ring building a quaternary ammonium system. The structure of 1 was established by spectroscopic analysis of the parent compound and degradation products. The occurrence of a pyridazine ring in microbial secondary metabolites is unique.

View full abstract

Carbazomycins G (I) and H (II), new congeners of the carbazomycin complex, have been isolated from the culture broth of Streptoverticillium ehimense. They have proved to contain a unique quinol moiety in the molecule. Their structures have been elucidated by mass and NMR spectrometries and X-ray crystallographic analysis. Carbazomycin G showed moderate antifungal activity against Trichophyton species.

View full abstract

The antimycoplasmal activities of the pseudomonic acids isolated from Pseudomonas fluorescens NCIB 10586 are reported. Structure-activity relationships of a variety of ester, amide and thiol ester derivatives of the nucleus, monic acid A, are described. Enhanced antimycoplasmal activity is reported for a number of monic acid A esters and the most potent derivative, m-nitrobenzyl monate A, is a 100-fold more active against Mycoplasma hyopneumoniae than pseudomonic acid A.

View full abstract

Several acyl derivatives of hitachimycin have been synthesized and their activities, including antibacterial, cytocidal against HeLa cells and in vivo antitumor against sarcoma 180, evaluated. Some of these derivatives showed higher antitumor activity than hitachimycin. Among the derivatives, 11-O-propionyl-15-O-butyrylhitachimycin (12) and the 11-O-acylhitachimycins (15-17) were most effective in in vivo assay.

View full abstract

Antibiotic nonproducing variants of Streptomyces lasaliensis NRRL 3382R, which makes the polyether antibiotic lasalocid A (Las) and the quinoxaline antibiotic echinomycin (Ech), arose at a frequency of 3- 11 % after treatment with three different mutagens or regeneration of protoplasts compared with a spontaneous frequency of <0.1 %. Cosynthesis of lasalocid A was not observed upon testing a large number of Las- mutants in different pair-wise combinations, nor did these mutants accumulate probable intermediates of lasalocid A biosynthesis. These results suggest that loss of the las genes or their expression is induced at a high frequency by mutagenic treatments. In fusions of protoplasts of a strain with the las⁺ ech⁺ spo⁺ nic-1 rif-3 markers with strains bearing the Las^- Las^s Ech^- Bld^- (or spo⁺) str-1 markers, Las⁺ Ech⁺ Spo⁺ Str^R progeny were produced at a 61 - 89 % frequency compared with a 1 - 9 % frequency of Str^R antibiotic producing progeny with the nic-l or rif-3 genotypes. The more frequent restoration of antibiotic production than prototrophy or rifampicin sensitivity indicates that these antibiotic characters did not behave as normal chromosomal markers. Therefore the genetic instability might be due to the involvement of a plasmid in antibiotic production. The apparent lack of infectious transfer of the Las⁺ character to Las^- parents in conjugal matings between the few strains tested and no correlation between the presence of a large plasmid, pKSL, and lasalocid A production in several strains of S. lasaliensis do not favor the latter hypothesis, but they do not conclusively disprove it. Consequently, we suggest that a plasmid or another mobile genetic element is controlling antibiotic production in S. lasaliensis.

View full abstract

Fe(II)-Bleomycin is activated in air to form an electron paramagnetic resonance (EPR)-active species, termed "activated bleomycin¹⁾", that cleaves DNA, when present. When DNA is absent, the potential DNA cleavage activity is lost and the drug becomes self inactivated. A method is described for the preparation and purification of this self-inactivated product from bleomycin A₂, together with some of its physical properties. It is shown that the loss of DNA cleavage activity parallels an alteration of bithiazole fluorescence, attributed to chemical change at this residue. EPR evidence is brought forth that the Cu(II) binding site of inactivated bleomycin in not altered, nor is the ability to form a species with Fe(II) and O₂ having the identical spectroscopic signature as activated bleomycin.

View full abstract

Terpentecin at a concentration of 0, 78 μg/ml decreased the number of viable cells of Escherichia coli NIHJ to less than one thousandth the starting number in an hour when added to an exponentially growing culture in a nutrient broth. During this time, the turbidity of the cell suspension kept increasing as fast as the control. Microscopic inspection of the cells exposed to terpentecin under these conditions revealed that the cells were elongated. Terpentecin at a concentration of 6.25 μg/ml inhibited incorporation of [¹⁴C]thymidine into the acid-insoluble material of cells of E. coli NIHJ by 70% in 30 minutes in contrast to little or no inhibition of the incorporation of [¹⁴C]uridine or [¹⁴C]leucine. Under similar conditions, terpentecin did not inhibit either membrane transport (uptake) of [¹⁴C]thymidine into the cells or the metabolic conversion of the precursor into various cellular acid-soluble components. Terpentecin at a higher concentration (70 μg/ml) inhibited by 40% in 30 minutes the incorporation of [methyl-³H]thymidine triphosphate into the DNA fraction of toluenetreated cells of E. coli JE6296 (pol A^-). Terpentecin showed stronger antibacterial activities against Bacillus subtilis M45T (rar^-) and E. coli BE1121 (rec A^-) than against their corresponding wild type strains. However, terpentecin showed no mutagenicity by the Ames test with Salmonella typhimuriutn strains TA100, TA98, TA92, TA1538, TA1537 and TA1535, and with E. coli WP2 (uvr A).
Terpentecin at a lower concentration (0.07 μg/ml) inhibited growth in vitro of mouse leukemia L1210 cells by 50%. With the mammalian cells again the incorporation of [¹⁴C]thymidine into the acid-insoluble cell material was inhibited more strongly than incorporation of [¹⁴C]uridine and [¹⁴C]leucine. There was no sign of mutagenicity by the micronucleus test using mice.

View full abstract

DNA binding characteristics of ditrisarubicin B were studied by the fluorescence titration technique. Ditrisarubicin B bound to calf thymus DNA with an affinity higher than any we have ever seen among anthracyclines. The apparent association constant (K_app) of ditrisarubicin B was 2.36 × 10⁸ M^-1, which is 22.7 times larger than that of doxorubicin. The apparent number of binding sites (n_app) of ditrisarubicin B per nucleotide of DNA was 0.164, and this value is identical with that of doxorubicin. Betaclamycin A, which has a trisaccharide chain at C-7 but no carbohydrate at C-10 in the aglycone, interacted with DNA to give a K_app of 5.92 ×10⁶ M^-1 and n_app of 0.178. These results suggest to us that the high affinity of ditrisarubicin B for DNA is caused by the existence of a glycosidic chain at C-10.

View full abstract

At concentrations below the MIC, paldimycin induced changes in Staphylococcus aureus 502A (UC 9116, ATCC 28417) which increased its sensitivity to serum. The enhanced sensitivity to serum was concentration dependent with the maximal sensitivity found when bacteria were grown in approximately 1/10 MIC of paldimycin. Within an 1-hour incubation, S. aureus 502A typically grew 1.5 - 2-fold in serum. Following exposure to paldimycin, however, approximately 30-50% of the bacteria were killed in serum. The paldimycin treated bacteria were not more susceptible to phagocytosis and killing by polymorphonuclear leukocytes. At the concentrations utilized, the Staphylococci were enlarged and had thickened cell walls. The organisms were still viable and replicating, but irregularities in cell division were observed in transmission electron micrographs.

View full abstract

Sub-inhibitory concentrations of lincomycin slightly inhibit growth of Escherichia coli carrying plasmid RP4 and cause a 2-fold increase in TEM-2 β-lactamase. To analyze this effect, cultures were pulse-labeled with [³H]leucine, chased with non-radioactive leucine and immunoprecipitated with anti-β-lactamase antiserum. The synthesis rate of β-lactamase was two times higher in inhibited cultures than in control cultures. No significant decrease of labeled enzyme occurred during the 30 minutes chase, indicating no degradation of β-lactamase. The rate of maturation of pre-β-lactamase was determined by measuring the decrease in the amount of pre-β-lactamase after a 1-minute labeling interval. There was no significant difference between the control and lincomycin-treated cultures, indicating that posttranslational translocation is not involved in the stimulation. Both plasmid encoded and chromosomally encoded TEM-1 β-lactamase increased in the presence of lincomycin. The effects of other protein synthesis inhibitors on the synthesis of TEM-1 β-lactamase were examined. The stimulation of β-lactamase synthesis by lincomycin appears to be specific for macrolide and related antibiotics and is not a general phenomenon resulting from partial inhibition of protein synthesis.

View full abstract

Deoxypheganomycin D, a specific inhibitor of mycobacteria, inhibits the growth in vitro of Mycobacterium smegmatis ATCC 607 (M. 607) bacteriostatically at concentrations as high as 7×10^-5M. It shows no cross-resistance to paromomycin, capreomycin, viomycin, streptothricin, kanamycin and streptomycin. Deoxypheganomycin D at 2.8×10^-7M where the cell growth of M. 607 is only partially inhibited does not significantly inhibit DNA, RNA or protein synthesis but leads to marked decrease (13 % of control) in [¹⁴C]glycerol-derived radioactivity in cell-walls. In the presence of 7×10^-6M deoxypheganomycin D, the influx of leucine but not thymidine is affected while the reverse is true with efflux. The data suggest that the effect of deoxypheganomycin D on M. 607 may be related to both the cell membrane and specific mycobacterial lipid like components of the cell-wall.

View full abstract