The inhibition in vitro of bacterial DNA polymerases and RNA polymerase by antimalarial 8-aminoquinolines and by chloroquine

Abstract

The effects of various 8-aminoquinolines, two of their hydroxylated potential metabolites, and chloroquine on the in vitro activities of DNA polymerase of Micrococcus luteus (Micrococcus lysodeikticus) and of Escherichia coli and RNA polymerase of E. coli were determined. The antimalarial 8-aminoquinolines (including primaquine, and two hydroxylated potential metabolites) inhibited the activity of each bacterial DNA polymerase, and the levels of inhibition were not decreased appreciably by increasing the DNA concentration. Although the inhibition by chloroquine of the DNA polymerases was markedly decreased as the Mg 2+ concentration was increased, the inhibition by the 8-aminoquinolines was insensitive or only moderately sensitive to variations in the Mg 2+ concentration. At low Mg 2+ concentrations (0.3–0.6 mM), the inhibition of the DNA polymerases by chloroquine exceeded the inhibition by any of the 8-aminoquinolines but at higher Mg 2+ concentrations (1.4–7.0 mM) the inhibition by several of the 8-aminoquinolines approached or exceeded the inhibition by chloroquine. The inhibition of M. luteus DNA polymerase by the hydroxylated 8-aminoquinolines and chloroquine was markedly decreased by increases in the polymerase concentration. For M. luteus DNA polymerase, it was concluded that the inhibition was predominantly due to the interaction of aminoquinolines with the polymerase although a lesser contribution from the interaction of the aminoquinolines with the template (or primer) DNA was not excluded. No differences were observed in the inhibition of E. coli DNA polymerase by samples of dextrorotatory, levorotatory, and racemic chloroquine. With the exception of chloroquine and pentaquine, the aminoquinolines had little effect on the activity of E. coli RNA polymerase, and the inhibition of RNA polymerase was much less than the inhibition of the DNA polymerases.