<i>Plasmodium</i> IspD (2-C-Methyl-<scp>d</scp>-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target

Imlay, Leah; Armstrong, Christopher M.; Masters, Mary Clare; Li, Ting; Price, Kathryn E.; Edwards, Rachel L.; Mann, Katherine M.; Li, Lucy X.; Stallings, Christina L.; Berry, Neil G.; O’Neill, Paul M.; Odom, Audrey R.

doi:10.1021/id500047s

Cited by 45 publications

(64 citation statements)

References 57 publications

(124 reference statements)

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“…Wu et al (13) replicated this and went on to show that D6 directly inhibits 2-Cmethyl-D-erythritol 4-phosphate cytidylyltransferase (IspD), the third enzyme in the IPP pathway, and that IspD mutation confers resistance to this compound. Imlay et al (14) confirmed these findings and showed that D6 competes with the CTP-binding site of IspD. These studies confirm that D6 targets the production of IPP intermediates in the apicoplast and provide independent evidence for the mechanism of cMEPP depletion observed in this metabolomics screen.…”

Section: Figsupporting

confidence: 72%

“…Enzymes involved in IPP biosynthesis are validated drug targets and existing IPP inhibitors, such as fosmidomycin (inhibitor of 1-deoxyxylulose 5-phosphate reductoisomerase), also lead to depletion of cMEPP (21). Recent studies have provided independent confirmation that D6 inhibits IPP biosynthesis (12)(13)(14). Bowman et al (12) utilized an isoprenoid-supplemented culture medium to test the activity of Malaria Box compounds and identified D6 as the only compound that displayed reduced activity in the supplemented medium compared to that in standard culture conditions.…”

Section: Figmentioning

confidence: 99%

“…Screens against specific parasite proteins have identified inhibitors of kinesin-5 (7), thioredoxin reductase (8), parasite aminopeptidases (9), dihydrofolate reductase-thymidylate synthase (10), and deoxyhypusine hydroxylase (11). Analysis of the activity of these compounds in the presence of isoprenoid precursors has identified compounds that exert their action by inhibition of isoprenoid biosynthesis in the apicoplast (12)(13)(14). A beta-hematin inhibition assay identified 10 compounds that inhibit the heme detoxification pathway (15), and the activity of one compound appears to be related to autophagy (16).…”

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confidence: 99%

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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: Figsupporting

confidence: 72%

Section: Figmentioning

confidence: 99%

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confidence: 99%

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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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“…Imlay et al (2015) found that Plasmodium IspD could also be an easy intracellular target of MMV008138.…”

Section: Results and Discussion:-mentioning

confidence: 99%

Inhibition of Ispd Enzyme to Control the Growth of Mycobacterium Tuberculosis.

Kumar¹,

Kumar²,

Kumari³

et al. 2017

IJAR

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“…More recently, a chemical rescue screen identified 4 (1 R ,3 S -MMV008138) from the Medicines for Malaria Venture (MMV) “malaria box” as a potent inhibitor of P. falciparum IspD ( Pf IspD), showing nanomolar inhibition of recombinant enzyme activity and sub-micromolar inhibition of parasite growth (Fig. 2)19202122.…”

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confidence: 99%

Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

Price

Armstrong

Imlay

et al. 2016

Sci Rep

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The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC50 values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria.

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Plasmodium IspD (2-C-Methyl-d-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target

Cited by 45 publications

References 57 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

Inhibition of Ispd Enzyme to Control the Growth of Mycobacterium Tuberculosis.

Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

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