Possible basis for the dichotomy in the action of DNA gyrase inhibitors on eukaryotes

Abstract

A number of recent studies have suggested that inhibitors of bacterial DNA gyrase such as nalidixic acid (NAL) and novobiocin possessed genotoxic, DNA-inhibitory and teratogenic properties (Kowalczyk, 1980; McCoy et al., 1980; Czinn et al., 1981; Collins and Johnson, 1979; Lavin, 1981; Mattern and Painter, 1979; Crumplin, 1981; Von Wright and Bridges, 1981). In addition evidence has also been obtained that eukaryotic cells contained DNA gyrase-like enzymes (e.g., topoisomerases II) that are sensitive to inhibition by blockers of DNA gyrase (Baldi et al., 1980; Cozzarelli, 1980; Hsieh and Brutlag, 1980; Liu et al., 1980). Because these findings suggest that inhibitors of putative eukaryotic DNA topoisomerases II might induce genotoxic and developmental effects, it was thought of interest to investigate further the biochemical basis of the effects of NAL, a useful anti-infective agent, on eukaryotic systems. The present study deals with the metabolic effects of NAL on the developing American sea-urchin embryo. It had been shown previously that NAL interfered with sea-urchin development mainly at or following blastulation (Czinn et al., 1981) which was also found to be the stage of embryogenesis susceptible to inhibition by novobiocin and hydroxyurea. Both hydroxyurea and novobiocin inhibit sea-urchin DNA synthesis (Eisenberg et al., 1965; Speck et al., 1982). But while hydroxyurea blocks nucleoside diphosphate reductase, novobiocin is thought to act on a topoisomerase as well as on DNA polymerase (see below). Moreover, while the principal effect of hydroxyurea was blockage of DNA synthesis, which was accompanied by a slight inhibition in RNA synthesis and no effect on protein production; novobiocin-mediated inhibition of DNA synthesis was accompanied by a significant stimulation of protein synthesis (Speck et al., 1982).