Synergistic action between PfHsp90 inhibitor and PfRad51 inhibitor induces elevated DNA damage sensitivity in the Malaria parasite

dc.contributor.author Tabassum, Wahida
dc.contributor.author Singh, Priyanka
dc.contributor.author Suthram, Niranjan
dc.contributor.author Bhattacharyya, Sunanda
dc.contributor.author Bhattacharyya, Mrinal Kanti
dc.date.accessioned 2022-03-27T05:18:58Z
dc.date.available 2022-03-27T05:18:58Z
dc.date.issued 2021-09-01
dc.description.abstract The DNA recombinase Rad51 from the human malaria parasite Plasmodium falciparum has emerged as a potential drug target due to its central role in the homologous recombination (HR)-mediated double-strand break (DSB) repair pathway. Inhibition of the ATPase and strand exchange activity of P. falciparum Rad51 (PfRad51) by a smallmolecule inhibitor, B02 [3-(phenylmethyl)-2-[(1E)-2-(3-pyridinyl)ethenyl]-4(3H)-quinazolinone], renders the parasite more sensitive to genotoxic agents. Here, we investigated whether the inhibition of the molecular chaperone PfHsp90 potentiates the antimalarial action of B02. We found that the PfHsp90 inhibitor 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] exhibits strong synergism with B02 in both drug-sensitive (strain 3D7) and multidrug-resistant (strain Dd2) P. falciparum parasites. 17-AAG causes a greater than 200-fold decrease in the half-maximal inhibitory concentration (IC50) of B02 in 3D7 parasites. Our results provide mechanistic insights into such profound synergism between 17- AAG and B02. We report that PfHsp90 physically interacts with PfRad51 and promotes the UV irradiation-induced DNA repair activity of PfRad51 by controlling its stability. We find that 17-AAG reduces PfRad51 protein levels by accelerating proteasomal degradation. Consequently, PfHsp90 inhibition renders the parasites more susceptible to the potent DNA-damaging agent methyl methanesulfonate (MMS) in a dose-dependent manner. Thus, our study provides a rationale for targeting PfHsp90 along with the recombinase PfRad51 for controlling malaria propagation.
dc.identifier.citation Antimicrobial Agents and Chemotherapy. v.65(9)
dc.identifier.issn 00664804
dc.identifier.uri 10.1128/AAC.00457-21
dc.identifier.uri https://journals.asm.org/doi/10.1128/AAC.00457-21
dc.identifier.uri https://dspace.uohyd.ac.in/handle/1/8025
dc.subject 17-AAG
dc.subject B02
dc.subject PfHsp90
dc.subject PfRad51
dc.subject Plasmodium DNA repair
dc.subject Synergy between 17-AAG and B02
dc.title Synergistic action between PfHsp90 inhibitor and PfRad51 inhibitor induces elevated DNA damage sensitivity in the Malaria parasite
dc.type Journal. Article
dspace.entity.type
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