SELECTIVE-INHIBITION OF TOPOISOMERASES FROM PNEUMOCYSTIS-CARINII COMPARED WITH THAT OF TOPOISOMERASES FROM MAMMALIAN-CELLS

Type I and II topoisomerase activities were partially purified from Pn eumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationi c-substituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin. The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P. carinii pneumonia. Selected dicationic-substituted bis-benzimid azoles also strongly inhibited the induction of the topoisomerase I- a nd II-mediated cleavable complex, suggesting that the biologically act ive DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivitie s for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that the se compounds hold promise as effective therapeutic agents in the treat ment of a life-threatening AIDS-related disease, P. carinii pneumonia.