Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Klonis, Nectarios; Creek, Darren J.; Tilley, Leann

doi:10.1016/j.mib.2013.07.005

Cited by 104 publications

(87 citation statements)

References 51 publications

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“…The specific mode of action of the artemisinins is a matter of debate but is thought to involve iron-mediated activation of the peroxide bond to produce free radicals that induce nonspecific parasite damage (46). The significant impact of artemisinin on intracellular levels of hemoglobin peptides and other metabolites a Pearson correlation between relative metabolite abundances for compounds compared to artemisinin (using average values from the three independent artemisinin experiments), quinolines (using average values from chloroquine and piperaquine experiments), and atovaquone (using average values from the three independent atovaquone experiments).…”

Section: Resultsmentioning

confidence: 99%

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Creek

Chua

Cobbold

et al. 2016

Antimicrob Agents Chemother

130

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e High-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remains unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations in in vitro cultures of Plasmodium falciparum. In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways, such as isoprenoid biosynthesis (i.e., 2-C-methyl-D-erythritol 2,4-cyclodiphosphate) and linolenic acid metabolism (i.e., traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs. Malaria remains a major global health problem, and there is a pressing need to discover and develop new antimalarials. Traditional antimalarial drugs have been severely undermined by the emergence of drug-resistant strains and current treatments rely heavily on artemisinin-based combination therapies. Alarmingly, artemisinin resistance has arisen in Southeast Asia during the last decade, highlighting the urgent need for new antimalarials (1). Extensive efforts to produce a malaria vaccine have met limited success and a pipeline of new antimalarial drugs will be required to mitigate extensive morbidity and mortality from malaria for the foreseeable future (2).High-throughput phenotypic screening of chemical libraries against the malaria parasite, Plasmodium falciparum, has provided a major step forward in the discovery of novel antimalarial compounds. Almost 30,000 compounds that selectively inhibit growth of cultured P. falciparum asexual red blood cell (RBC) stages have been identified in these screens, providing excellent starting points for the discovery of new antimalarial drugs (3-5). A prioritized collection of these "hit" compounds, known as the Malaria Box, has been assembled by the Medicines for Malaria Venture (MMV) and provided free to the research community to facilitate this drug development pipeline (6).A key limitation to the further optimization of many of these compounds is the lack of information on their mode of action. While not essential for registration, information on the mode of action of inhibitors discovered in phenotypic screens will significantly accelerate drug development by allowing structure-based drug design, monitoring of activity, toxicity and resistance, and facilitation of rational clinical usage in combination with other medicines. Furthermore, in...

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Section: Resultsmentioning

confidence: 99%

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Creek

Chua

Cobbold

et al. 2016

Antimicrob Agents Chemother

130

View full text Add to dashboard Cite

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“…Much effort is still expended in the elucidation of the modes of action in both Plasmodium falciparum (38)(39)(40) and yeast (41)(42)(43). A yeast model uncovered a role of mitochondria during the action of artemisinins with an important function for the electron transport chain and subsequent damage by locally generated ROS (41).…”

Section: Resultsmentioning

confidence: 99%

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Cremer

Lanckacker

Cools

et al. 2015

Antimicrob Agents Chemother

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cMucosal biofilm-related fungal infections are very common, and the incidence of recurrent oral and vulvovaginal candidiasis is significant. As resistance to azoles (the preferred treatment) is occurring, we aimed at identifying compounds that increase the activity of miconazole against Candida albicans biofilms. We screened 1,600 compounds of a drug-repositioning library in combination with a subinhibitory concentration of miconazole. Synergy between the best identified potentiators and miconazole was characterized by checkerboard analyses and fractional inhibitory concentration indices. Hexachlorophene, pyrvinium pamoate, and artesunate act synergistically with miconazole in affecting C. albicans biofilms. Synergy was most pronounced for artesunate and structural homologues thereof. No synergistic effect could be observed between artesunate and fluconazole, caspofungin, or amphotericin B. Our data reveal enhancement of the antibiofilm activity of miconazole by artesunate, pointing to potential combination therapy consisting of miconazole and artesunate to treat C. albicans biofilm-related infections.

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“…A prominent phenotype of P. falciparum lines selected for resistance to artemisinins is ring stage quiescence (Witkowski et al, 2010): a temporary arrest of development and hemoglobin uptake and heme/hematin release until toxic ART levels have been reduced sufficiently to resume growth (Klonis et al, 2013a). Sensitive parasites appear to also be able to enter the dormant stage, albeit at a reduced frequency compared to in vitro -derived resistant lines, suggesting that resistant lines have multiple means to withstand ART exposure (Teuscher et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Supergenomic Network Compression and the Discovery of EXP1 as a Glutathione Transferase Inhibited by Artesunate

Lisewski

Quiros

et al. 2014

Cell

113

128

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Summary A central problem in biology is to identify gene function. One approach is to infer function in large supergenomic networks of interactions and ancestral relationships among genes; however, their analysis can be computationally prohibitive. We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks. Compression enables global network analysis to computationally harness hundreds of interconnected genomes and to produce functional predictions. As a demonstration, we show that the essential, but functionally uncharacterized Plasmodium falciparum antigen EXP1 is a membrane glutathione S-transferase. EXP1 efficiently degrades cytotoxic hematin, is potently inhibited by artesunate, and is associated with artesunate metabolism and susceptibility in drug-pressured malaria parasites. These data implicate EXP1 in the mode of action of a frontline antimalarial drug.

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Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Cited by 104 publications

References 51 publications

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Supergenomic Network Compression and the Discovery of EXP1 as a Glutathione Transferase Inhibited by Artesunate

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