ENERGY-DEPENDENT MITOCHONDRIAL MUTAGENICITY OF ANTIBACTERIAL OFLOXACIN AND ITS RECOMBINOGENIC ACTIVITY IN YEAST

Ofloxacin, a specific inhibitor of bacterial topoisomerase II, is know n to inhibit the growth of yeast cells and to induce rho(-) mutants in the yeast S. cerevisiae. The frequency of ofloxacin-induced petite mu tants under non-growth conditions was found to be strongly diminished when the cells were depleted in intramitochondrial ATP. Under optimal conditions of mitochondrial mutagenesis the drug induced mitotic recom bination and reverse mutation in diploid strains but failed to cure ei ther killer plasmids or the 2 mu m DNA of dividing cells. The sensitiv ity to ofloxacin of the strains deficient in the DNA strand-break repa ir pathway (rad52) was significantly higher then that of the wild-type strains and of the mutants deficient in excision or mutagenic DNA rep air. The results are compatible with the idea that the cytotoxic and g enetic activity of ofloxacin in yeast probably results from the inhibi ted DNA ligation function of topoisomerase II creating DNA breaks that are reparable through the recombination repair pathway.