Linkers designed to intercalate the double helix greatly facilitate DNA alkylation by triplex-forming oligonucleotides carrying a cyclopropapyrroloindole reactive moiety. (1/244)

Triplex-forming oligonucleotides (TFOs) bind sequence-specifically in the major groove of double-stranded DNA. Cyclopropapyrroloindole (CPI), the electrophilic moiety that comprises the reactive subunit of the antibiotic CC-1065, gives hybridization-triggered alkylation at the N-3 position of adenines when bound in the minor groove of double-stranded DNA. In order to attain TFO-directed targeting of CPI, we designed and tested linkers to 'thread' DNA from the major groove-bound TFO to the minor groove binding site of CPI. Placement of an aromatic ring in the linker significantly enhanced the site-directed reaction, possibly due to a 'threading' mechanism where the aromatic ring is intercalated. All of the linkers containing aromatic rings provided efficient alkylation of the duplex target. The linker containing an acridine ring system, the strongest intercalator in the series, gave a small but clearly detectable amount of non-TFO-specific alkylation. An equivalent-length linker without an aromatic ring was very inefficient in DNA target alkylation.  (+info)

Plasmid copy number control: isolation and characterization of high-copy-number mutants of plasmid pE194. (2/244)

A plasmid, pE194, obtained from Staphylococcus aureus confers resistance to macrolide, lincosamide, and streptogramin type B ("MLS") antibiotics. For full expression, the resistance phenotype requires a period of induction by subinhibitory concentrations of erythromycin. A copy number in the range of 10 to 25 copies per cell is maintained during cultivation at 32 degrees C. It is possible to transfer pE194 to Bacillus subtilis by transformation. In B. subtilis, the plasmid is maintained at a copy number of approximately 10 per cell at 37 degrees C, and resistance is inducible. Tylosin, a macrolide antibiotic which resembles erythromycin structurally and to which erythromycin induces resistance, lacks inducing activity. Two types of plasmid mutants were obtained and characterized after selection on medium containing 10 microgram of tylosin per ml. One mutant class appeared to express resistance constitutively and maintained a copy number indistinguishable from that of the parent plasmid. The other mutant type had a 5- to 10-fold-elevated plasmid copy number (i.e., 50 to 100 copies per cell) and expressed resistance inducibly. Both classes of tylosin-resistant mutants were shown to be due to alterations in the plasmid and not to modifications of the host genome.  (+info)

Characterization of a duocarmycin-DNA adduct-recognizing protein in cancer cells. (3/244)

Duocarmycins have been reported to derive their potent antitumor activity through a sequence-selective minor groove alkylation of N3 adenine in double-stranded DNA. We have used gel mobility shift assays to detect proteins that bind to DNA treated in vitro with duocarmycin SA and identified a protein, named duocarmycin-DNA adduct recognizing protein (DARP), which binds with increased affinity to duocarmycin-damaged DNA. Examination with partially purified DARP revealed that the protein recognized not only the DNA adduct of structurally related drug, CC-1065, but unexpectedly, the protein also recognized the DNA adduct of another chemotype of minor groove binder, anthramycin. These results demonstrate that DARP recognizes the structural alteration of DNA induced by these potent DNA-alkylating drugs, suggesting the possibility that the protein might modulate the antitumor activity of these drugs.  (+info)

In vitro activity of rosamicin, josamycin, erythromycin, and clindamycin against beta-lactamase-nagative and beta-lactamase-positive strains of Neisseria gonorrhoeae. (4/244)

Randomly selected strains of beta-lactamase-negative and beta-lactamase-positive Neisseria gonorrhoeae were tested by an agar dilution method for susceptibility to rosamicin, josamycin, erythromycin, clindamycin, and penicillin G. Rosamicin was more active than erythromycin, which was more active than josamycin or clindamycin; the latter two were similar in their activity. The susceptibility to the macrolide antibiotics and clindamycin was independent of beta-lactamase production, but the penicillin minimal inhibitory concentrations were higher in the beta-lactamase-positive group because of the enzyme.  (+info)

Inhibitors of protein synthesis V. Irreversible interaction of antibiotics with an initiation complex. (5/244)

The initiation complex (t-complex) formed in a cell-free system (E. coli) from Ac-Phe-tRNA, poly(U) and washed ribosomes in the presence of initiation factors (ribosomal wash) and GTP, contains the Ac-Phe-tRNA bound quantitatively in a puromycin-reactive state. The t-complex is irreversibly inactivated by spiramycin with respect to its reactivity toward puromycin. The inactivated t-complex retains all of the Ac-Phe-tRNA bound, but it does not react with puromycin (2 x10-minus-3M) within 32 min at 25 degrees. In the case of another inhibitor protein synthesis, sparsomycin, the permanently "modified" t-complex not only retains all the bound Ac-Phe-tRNA but it can still react with puromycin. In the continuous presence of sparsomycin (1 x 10-minus-7M) the bound Ac-Phe-tRNA reacts quantitatively at a rate which is one-tenth the rate at which the t-complex reacts with puromycin, at low (6.25 x 10-minus-5M) or high (2 x 10-minus-3M) concentrations. These results are not in agreement with current views according to which aparsomycin binds to the ribosome reversibly at a single site with a KI in the range of 10-minus6-10-minus-7 M and according to which this stie is at the A'-site (puromycin site) of peptidyl transferase.  (+info)

The effect of feeding diets containing permitted antibiotics on the faecal excretion of Salmonella typhimurium by experimentally infected chickens. (6/244)

Groups of 45 chickens were fed continuously on diets containing 10 or 100 mg./kg. of different 'growth-promoting' antibiotics and infected orally with a nalidixic acid-resistant mutant of Salmonella typhimurium. The amount of S. typhimurium organisms excreted in their faeces was estimated by culturing them at weekly intervals and in a standard manner on plates of brilliant green agar containing sodium nalidixate, both direct and after enrichment in selenite broth. All of four groups fed diets containing 100 mg./kg. of nitrovin in three different experiments excreted much larger amounts of S. typhimurium than did groups fed antibiotic-free diets. In some, but not all, experiments, larger amounts were also excreted by groups fed diets containing 10 mg./kg. of nitrovin or 10 or 100 mg./kg. of flavomycin or tylosin. Feeding diets containing 10 or 100 mg./kg. of virginiamycin or bacitracin either did not influence or slightly increased the amount of S. typhimiurium excreted. Two groups fed continuously on diets containing 100 or 500 mg./kg. of sulphaquinoxaline for 44 days excreted smaller amounts of the S. typhimurium organisms that did groups fed antibiotic-free diets; no sulphonamide-resistant organisms of the S. typhimurium strain were isolated from the faeces.  (+info)

In vitro comparison of rosamicin and erythromycin against urinary tract pathogens. (7/244)

The in vitro activity of rosamicin and erythromycin was compared at various pH values against 311 strains of bacteria representing common urinary tract pathogens. Alkalinization of the media consistently and significantly increased the antibacterial activity of rosamicin against all of the organisms tested. This was also true for erythromycin except when tested against strains of Proteus. At pH 8, rosamicin was two- to sixfold more active than erythromycin against Enterobacteriaceae. The activity of both antibiotics against Pseudomonas aeruginosa was very similar when tested at pH 8. Erythromycin was twice as active as rosamicin at pH 8 against group D streptococci. The activity of both antibiotics was bacteriostatic and inoculum size dependent, regardless of the organism tested or the pH of the test media. The greater activity of rosamicin against Enterobacteriaceae warrants clinical investigation.  (+info)

I. Isolation and characterization of the transformation products of maridomycin III. (8/244)

Three transformation products of maridomycin (MDM) III, a macrolide antibiotic, by Streptomyces lavendulae were isolated by silica gel and alumina chromatography, and designated as spots 1 (starting MDM III), 2, 3 and 4, in the order of their decreasing Rf values on thin-layer chromatogram. By mass- and NMR-spectrometry and thin-layer chromatography, spot 2 was identified as 18-dihydro-MDM III, spot 3 as 4''-depropionyl-MDM III, and spot 4 as 18-dihydro-4''-depropionyl-MDM III. The relationship between starting MDM III and these transformation products were also discussed.  (+info)

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