Abstract
The mode of action of SQ18506 (a 5-nitrofuran) against Trypanosoma cruzi, a protozoan, was found in previous studies to be inhibition of nucleic acid synthesis. To find out how this inhibition occurred, we systematically investigated the effect of the drug on three components of nucleic acid synthesis: uptake and metabolism of nucleic acid precursors, nucleic acid polymerases, DNA template. In vitro, SQ18506 inhibited both DNA and RNA polymerases and interacted with DNA. Thus, at physiological drug concentrations there was marked inhibition of the polymerases which was increased in the presence of a nitro-reducing system. SQ18506 also decreased the T m of calf thymus DNA by up to 5°. In vivo, the drug caused single strand breaks within 1 hr of incubation and double strand breaks by 7.5 hr in the DNA of T. cruzi. Thus, inhibition of nucleic acid synthesis may be the result of a combination of lesions, though whether it is actually responsible for the cell lysis which is the culmination of the effect of the drug remains undecided.
Published Version
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