Inhibition of Plasmodium DNA double strand repair by the combined action of 17-AAG and ML216

The RecQ helicase PfBlm from the human malaria parasite Plasmodium falciparum plays a critical role in maintaining genome integrity through its function in homologous recombination mediated DNA repair. Given its essential role in resolving recombination intermediates, PfBlm has emerged as a potential antimalarial drug target. Chemical inhibition of PfBlm helicase activity using the small-molecule inhibitor ML216 sensitize the parasites towards DNA damage inducing agents. Here, we investigated whether inhibition of the molecular chaperone PfHsp90 enhances the antimalarial efficacy of ML216. We demonstrate that the co-treatment with 17-AAG resulted in a marked reduction in the IC 50 of ML216, indicating potentiation of PfBlm inhibition upon PfHsp90 targeting. We report that PfHsp90 functionally associates with PfBlm and promotes UV irradiation–induced DNA repair by regulating PfBlm stability. Combined inhibition of PfHsp90 and PfBlm caused a pronounced and sustained defect in DNA repair that exceeded the effects of each of the individual inhibitors, consistent with a functional interaction. Together, these findings suggest that PfHsp90 contributes to PfBlm stability and activity, thus provide a rationale for simultaneously targeting PfHsp90 and PfBlm as a strategy to block parasite DNA repair and limit parasite survival.