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Radicicol confers mid-schizont arrest by inhibiting mitochondrial replication in Plasmodium falciparum.

ABSTRACT: Radicicol, 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.

SUBMITTER: Chalapareddy S

PROVIDER: S-EPMC4136038 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Radicicol confers mid-schizont arrest by inhibiting mitochondrial replication in Plasmodium falciparum.

Chalapareddy Sureshkumar S Bhattacharyya Mrinal Kanti MK Mishra Seema S Bhattacharyya Sunanda S

Antimicrobial agents and chemotherapy 20140519 8

Radicicol, 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 ...[more]

PMID: 24841259

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Project description:Background: Malaria is a one of the most important infectious diseases and is caused by parasitic protozoa of the genus Plasmodium. Previously, the quantitative characterization of the P. falciparum transcriptome demonstrated that the strictly controlled progression of these parasites through their intra-erythrocytic developmental cycle is accompanied by a continuous cascade of gene expression. Although such analyses have proven immensely useful, the precise correlations between transcript and protein abundance remain under-scrutinized. Results: Here, we present a quantitative time-course analysis of relative protein abundance for schizont-stage parasites (34-46 hours post-invasion) based on 2D-gel electrophoresis of protein samples labeled with DIGE fluorescent dyes. For this purpose we analyzed parasite samples taken at four-hour intervals from a tightly synchronized culture and established more than 500 individual protein abundance profiles with high temporal resolution and quantitative reproducibility. Approximately half of all profiles exhibit a significant change in abundance and 12% display an expression peak during the observed 12-hour time interval. Intriguingly, identification of 54 protein spots by mass spectrometry revealed that 58% of the corresponding proteins including actin-I, enolase, eIF4A, eIF5A, and several heat shock proteins are represented by more than one isoform, presumably due to post-translational modifications, with the various isoforms of a given protein frequently showing different expression patterns. Furthermore, comparisons with transcriptome data generated from the same parasite samples reveal significant post-transcriptional gene expression regulation. Conclusions: Together, our data indicate that both post-transcriptional and post-translational events are widespread and of presumably great biological significance during the intra-erythrocytic development of P. falciparum. Additional comment: In essence, the microarray data generated in this study is a repeat of the transcriptome analysis described in Bozdech et al., PLoS Biol 2003, 1(1):E5. Differences include (1) an improved set of oligonucleotides [see Hu et al., BMC Bioinformatics 2007, 8:350] used in the study associated with this GEO entry, and (2) the sampling at only four timepoints during the intra-erythrocytic development cycle (schizont stage) to match and complement the samples processed in the concomitant proteomics analysis.

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Radicicol confers mid-schizont arrest by inhibiting mitochondrial replication in Plasmodium falciparum.

Publications

Radicicol confers mid-schizont arrest by inhibiting mitochondrial replication in Plasmodium falciparum.

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