The mechanism of artemisinin resistance of <i>Plasmodium falciparum</i> malaria parasites originates in their initial transcriptional response

Zhu, Lei; Pluijm, Rob W van der; Kucharski, Michal; Nayak, Sourav; Tripathi, Jaishree; Nosten, François; Faiz, Abul; Amaratunga, Chanaki; Lek, Dysoley; Ashley, Elizabeth A.; Smithuis, Frank; Phyo, Aung Pyae; Lin, Khin; Imwong, Mallika; Mayxay, Mayfong; Dhorda, Mehul; Chau, Nguyen Hoang; Thuy, Nhien Nguyen Thanh; Newton, Paul N.; Jittamala, Podjanee; Tripura, Rupam; Pukrittayakamee, Sasithon; Peto, Thomas J.; Miotto, Olivo; Seidlein, Lorenz von; Hien, Tran Tinh; Ginsburg, Hagaï; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.; Bozdech, Zbynek

doi:10.1101/2021.05.17.444396

Cited by 2 publications

(1 citation statement)

References 68 publications

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“…P. falciparum is endemic throughout sub-Saharan Africa and much of Asia, and the disease is a major barrier to socio-economic development. Despite being managed in many parts of the world through a rigorous programme of insecticide spraying, insecticide-treated bed net distribution and antimalarial treatment, resistance to both insecticides and drugs commonly arises [2][3][4][5][6] and can spread rapidly [7]. Although current programmes of artemisinin-based combination therapy (ACT) have greatly reduced the clinical burden of malaria, more new drug targets are needed.…”

Section: Introductionmentioning

confidence: 99%

Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasitePlasmodium falciparum

Craven¹,

Nettesheim²,

Cicuta³

et al. 2023

Preprint

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Plasmodium falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to many drugs, including the current frontline treatments, so new therapeutic targets are needed. Our previous work on guanine quadruplexes (G4s) in the parasite's DNA and RNA has highlighted their influence on parasite biology, and revealed G4 stabilising compounds as promising candidates for drug repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive.

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Section: Introductionmentioning

confidence: 99%

Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasitePlasmodium falciparum

Craven¹,

Nettesheim²,

Cicuta³

et al. 2023

Preprint

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show abstract

PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum

Kanyal

Davies

Deshmukh

et al. 2022

Preprint

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Plasmodium falciparum is a deadly protozoan parasite and the causative agent of malaria, which accounts for close to 200 million cases and 400,000 deaths every year. It has been identified to possess a tightly regulated gene expression profile that is integrally linked to its timely development during the intraerythrocytic stage. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasite transcriptome. In this study, we characterize the solitary class I histone deacetylase PfHDAC1 and demonstrate that phosphorylation is required for its catalytic activity. PfHDAC1 binds to and regulates parasite genes responsible for housekeeping and stress-responsive functions. We show that PfHDAC1 activity in parasites is crucial for normal intraerythrocytic development and that its cellular abundance is correlated with parasitemia progression. We further show that PfHDAC1 has differential abundance and genomic occupancy in artemisinin drug-resistant vs sensitive parasites and that inhibition of its deacetylase activity can modulate the sensitivity of parasites to the drug. We also identify that artemisinin exposure can interfere with PfHDAC1 phosphorylation and its genomic occupancy. Collectively, our results demonstrate PfHDAC1 to be an important regulator of basic biological functions in parasites while also deterministic of responses to environmental stresses such as antimalarial drugs.

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The mechanism of artemisinin resistance of Plasmodium falciparum malaria parasites originates in their initial transcriptional response

Cited by 2 publications

References 68 publications

Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasitePlasmodium falciparum

Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasitePlasmodium falciparum

PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum

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