Radicicol Confers Mid-Schizont Arrest by Inhibiting Mitochondrial Replication in Plasmodium falciparum

Abstract

bRadicicol, an antifungal antibiotic, was previously identified as a compound having antimalarial activity. However, its mechanism of action in Plasmodium falciparum was not elucidated. While characterizing its antimalarial function, we observed that radicicol manifested two distinct developmental defects in cultured P. falciparum in a concentration-dependent manner. At a low concentration of radicicol, a significant percentage of drug-treated parasites were arrested at the schizont stage, while at a higher concentration, the parasites were unable to multiply from schizont to ring. Also, the newly formed rings and trophozoites were extremely delayed in development, eventually leading to cell death. We intended to characterize the potential molecular target of radicicol at its sublethal doses. Our results demonstrated that radicicol specifically impaired mitochondrial replication. This decrement was associated with a severalfold increment of the topoisomerase VIB transcript as well as protein in treated cells over that of untreated parasites. Topoisomerase VIB was found to be localized in the organelle fraction. Our docking study revealed that radicicol fits into the Bergerat fold of Pf topoisomerase VIB present in its ATPase domain. Altogether, these data allow us to conclude that P. falciparum topoisomerase VIB might be one of the targets of radicicol causing inhibition of mitochondrial replication. Hence, radicicol can be suitably employed to explore the mitochondrial physiology of malaria parasites.

Identification of Plasmodium falciparum DNA Repair Protein Mre11 with an Evolutionarily Conserved Nuclease Function

“…falciparum 3D7 culture having 10% parasitemia was synchronized using 5% sorbitol followed by harvesting at the ring, trophozoite and schizont stages were harvested. Total RNA was isolated from each stage specific culture with and without MMS treatment using the protocol as described [ 36 ]. Similarly, total RNA was isolated from yeast strains BSB1-BSB8 and PVY1 after incubation at 30°C using the acid-phenol method as described [ 33 ].…”

GEN3VA: aggregation and analysis of gene expression signatures from related studies

“…This pair of transcription factors has previously been identified to be involved in aging kidneys [37], and our analysis confirms a global pro-inflammatory mechanism. Finally, drugs that can potentially accelerate or attenuate aging include celastrol, which was reported to indirectly inhibit NFKB signaling [38, 39], and radicicol, which is potentially a HSP90 and topoisomerase inhibitor [40]. Both drugs are small-molecule natural compounds that could be tested for their effect on aging (Fig.…”

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

“…More specifically, it was observed that compound 1 strongly inhibits the erythrocytic form of W2 strain P. falciparum at nontoxic concentrations for mouse macrophages. In addition, compound 1 is able to prevent the parasite development into schizonts 27 and this was achieved without causing hemolysis. An examination of parasite morphology revealed that compound 1 inhibits the formation of hemozoin crystals inside the digestive vacuoles.…”