echinomycin and hedamycin

More than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the Kitasato Institute for Life Sciences, were screened against African trypanosomes. Ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin A, echinomycin, hedamycin, irumamycin, LL-Z 1272beta, O-methylnanaomycin A, venturicidin A and virustomycin A. Results of the in vitro assays using the GUTat 3.1 strain of Trypanosomal brucei brucei and the STIB900 strain of T. b. rhodesiense are presented. Cytotoxicity was determined using a human MRC-5 cell line. This is the first report of antitrypanosomal activities of the 10 microbial metabolites listed above.

Topics: Alkynes; Animals; Anthraquinones; Cell Line; Chromones; Echinomycin; Hygromycin B; Macrolides; Naphthoquinones; Soil Microbiology; Trypanocidal Agents; Trypanosoma brucei brucei; Venturicidins

Intercalating, minor groove binding, and covalently bonding drugs were evaluated by mobility shift assays for their ability to interfere with transcription factors binding to their respective DNA recognition sequences. The Cys2His2 zinc finger proteins EGR1, WT1, and NIL2A, the basic leucine-zipper protein wbJun/wbFos, and the minor groove binding protein hTBP were chosen as representative transcription factors. Their DNA recognition sites include G/C-rich, mixed, and A/T-rich sequences. The intercalators nogalamycin and hedamycin, and the G/C-specific minor groove binding drug chromomycin A3 were the most potent drugs, preventing transcription factor.DNA complex formation at concentrations less than 1 microM. Similar concentrations of chromomycin A3 disrupted preformed complexes while nogalamycin and hedamycin were 50-fold less potent if proteins were allowed to bind DNA prior to drug treatment. Echinomycin inhibited EGR1.DNA complex formation 50% at 5 microM but had little effect on the formation of NIL2A.DNA complexes. Conversely, doxorubicin was found to inhibit NIL2A complex formation 50% at less than 1 microM, but did not achieve this level of inhibition of EGR1/DNA complex formation even at 50 microM. The A/T-directed minor groove binding drugs, while inhibiting hTBP at submicromolar concentrations, had no effect on either EGR1 or NIL2A.

Topics: Anthraquinones; Base Sequence; Chromomycins; DNA; DNA-Binding Proteins; Echinomycin; Intercalating Agents; Leucine Zippers; Molecular Sequence Data; Nogalamycin; Oligodeoxyribonucleotides; Transcription Factors; WT1 Proteins; Zinc Fingers