acriflavine and diminazene-aceturate

Trypanosoma brucei E164 and a dyskinetoplastic derivative, Dysk164, were injected into mice that were treated subsequently with methylglyoxal-bis-guanylhydrazone, berenil, ethidium bromide, and acriflavine. Additionally, parasites were photoaffinity labeled with ethidium monoazide to effect covalent drug attachment prior to injection into animals. In all cases, killing of animals with E164 was blocked by the drug treatment, whereas killing due to Dysk164 was not. These findings are consistent with the view that the intact kinetoplast plays an essential role in the action of these drugs.

Topics: Acriflavine; Animals; Azides; Diminazene; Dose-Response Relationship, Drug; Drug Resistance; Ethidium; Female; Light; Mice; Mitochondria; Mitoguazone; Mutation; Parasitemia; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Dual laser flow cytofluorimetry has been used to compare accumulation of compounds representing three major classes of trypanocidal drugs by drug sensitive and drug resistant clones of Trypanosoma brucei brucei and T. b. rhodesiense. Clones selected for resistance to melarsoprol were shown to be cross-resistant in vivo to two diamidines, pentamidine and Berenil, but not to suramin. At 35 degrees C, bloodstream forms of these multidrug-resistant clones accumulated lower intracellular concentrations of the diamidines 4',6-diamidino-2-phenyl-indole (DAPI) and Hoechst 33342, the phenanthridine ethidium bromide, and the acridine acriflavine than drug sensitive parasites. Accumulation of all four drugs was saturable. Drug concentrations giving half-maximal rates of accumulation were increased in the resistant clones relative to the sensitive parent clones. The rate of DAPI accumulation by both resistant and sensitive parasites was strongly temperature dependent and increased sharply above 27 degrees C. Two distinct populations were resolved in mixtures of sensitive and resistant clones exposed to DAPI. Resistant and sensitive cells accumulated identical intracellular concentrations of DAPI following brief treatment with the detergent Triton X-100. The results suggest that alterations in the surface membrane of multidrug-resistant trypanosomes reduce accumulation of several drugs relative to drug sensitive parasites.

Topics: Acriflavine; Animals; Benzimidazoles; Diminazene; Drug Resistance; Ethidium; Flow Cytometry; Fluorescent Dyes; Humans; Indoles; Melarsoprol; Mice; Pentamidine; Suramin; Trypanocidal Agents; Trypanosoma brucei brucei

The accumulation of respiratory deficient (RD) mutants in Saccharomyces cerevisiae depended upon the mutagens used and upon the presence of the nuclear gene previously identified as MMC1 (one) which we showed to control the spontaneous and the erythromycin-induced RD mutability. In this paper data are reported about the accumulation of RD mutants in the presence of manganous ions (Mn++) and UV which was higher in the mmc1 (one) than in MMC1 strains. We found that the characters 'low spontaneous' and 'low induced' RD mutability by erythromycin, manganous ions and UV, were controlled by the same genetic determinant. In the presence of manganous ions, also the frequency of antibiotic resistant mutants capR and eryR was higher in the mmc1 strains. Moreover, the accumulation of RD mutants in the presence of berenil, 5-fluorouracil and basic fuchsin was higher in the mmc1 than in MMC1 strains. In contrast, RD mutants accumulation by acriflavine and ethidium bromide treatments did not appear affected by the MMC1 genetic constitution.

Topics: Acriflavine; Cell Nucleus; Diminazene; DNA, Fungal; DNA, Mitochondrial; Erythromycin; Ethidium; Fluorouracil; Gene Expression Regulation; Manganese; Mutagens; Rosaniline Dyes; Saccharomyces cerevisiae