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Restructured Mitochondrial-Nuclear Interaction in Plasmodium falciparum Dormancy and Persister Survival after Artemisinin Exposure

June 1, 2021 - 15:38 -- Open Access
Connelly SV, Manzella-Lapeira J, Levine ZC, Brzostowski J, Krymskaya L, Rahman RS, Ellis AC, Amin SN, Sá JM, Wellems TE
mBio. 2021 May 28:e0075321

Artemisinin and its semisynthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here, we provide evidence that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Restructured mitochondrial-nuclear associations and an altered metabolic state are consistent with stress from reactive oxygen species.

NOT Open Access | Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin

June 1, 2021 - 12:24 -- NOT Open Access
Chellan P, Avery VM, Duffy S, Land KM, Tam CC, Kim JH, Cheng LW, Romero-Canelón I, Sadler PJ
J Inorg Biochem. 2021 Jun;219:111408

Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized.

Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing

May 12, 2021 - 12:39 -- Open Access
Sutherland CJ, Henrici RC, Artavanis-Tsakonas K
FEMS Microbiol Rev. 2021 May 5;45(3):fuaa056

Studies of the susceptibility of Plasmodium falciparum to the artemisinin family of antimalarial drugs provide a complex picture of partial resistance (tolerance) associated with increased parasite survival in vitro and in vivo.

NOT Open Access | AaWRKY9 contributes to light- and jasmonate-mediated to regulate the biosynthesis of artemisinin in Artemisia annua

May 12, 2021 - 09:04 -- NOT Open Access
Fu X, Peng B, Tang K, et al.
New Phytol. 2021 May 1

Artemisinin, isolated from Artemisia annua L., is recommended as the preferred drug to fight malaria. Previous research showed that JA mediated promotion of artemisinin accumulation was dependent on light. However, the mechanism underlying the interaction of light and JA in the regulation of artemisinin accumulation is still unknown. We identified a WRKY transcription factor, AaWRKY9, using transcriptome analysis.

NOT Open Access | Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study

April 22, 2021 - 08:46 -- NOT Open Access
Uwimana A, Umulisa N, Lucchi NW, et al.
Lancet Infect Dis. 2021 Apr 14:S1473-3099(21)00142-0

Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether–lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes.

Molecular surveillance of drug resistance: Plasmodium falciparum artemisinin resistance single nucleotide polymorphisms in Kelch protein propeller (K13) domain from Southern Pakistan

April 14, 2021 - 07:48 -- Open Access
Najia Karim Ghanchi, Bushra Qurashi, Hadiqa Raees and Mohammad Asim Beg
Malaria Journal 2021 20:176, 7 April 2021

K13 propeller (k13) polymorphism are useful molecular markers for tracking the emergence and spread of artemisinin resistance in Plasmodium falciparum. Polymorphisms are reported from Cambodia with rapid invasion of the population and almost near fixation in south East Asia. The study describes single nucleotide polymorphisms in Kelch protein propeller domain of P. falciparum associated with artemisinin resistance from Southern Pakistan.

NOT Open Access | Carrageenan oligomers and salicylic acid act in tandem to escalate artemisinin production by suppressing arsenic uptake and oxidative stress in Artemisia annua (sweet wormwood) cultivated in high arsenic soil

April 6, 2021 - 14:17 -- NOT Open Access
Naeem M, Aftab T, Ansari AA, Khan MMA
Environ Sci Pollut Res Int. 2021 Apr 5

The present study is aimed to elucidate the effects of concomitant application of irradiated carrageenan (IC) oligomers and salicylic acid (SA) on Artemisia annua L. varieties, viz. "CIM-Arogya" (tolerant) and "Jeevan Raksha" (sensitive) exposed to arsenic (As) stress. Artemisia annua has been known for its sesqui-terpene molecule artemisinin, which is useful in curing malaria. The two compounds, IC and SA, have been established as effective plant growth-promoting molecules for several agricultural and horticultural crops. To test the stress tolerance providing efficacy of IC and SA, the characterization of various physiological and biochemical parameters, growth as well as yield attributes was done in the present experiment.

NOT Open Access | Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review

April 1, 2021 - 09:03 -- NOT Open Access
Kayiba NK, Yobi DM, Speybroeck N, et al.
Lancet Infect Dis. 2021 Apr;21(4):e82-e92

The spread of Plasmodium falciparum isolates carrying mutations in the kelch13 (Pfkelch13) gene associated with artemisinin resistance (PfART-R) in southeast Asia threatens malaria control and elimination efforts. Emergence of PfART-R in Africa would result in a major public health problem. In this systematic review, we investigate the frequency and spatial distribution of Pfkelch13 mutants in Africa, including mutants linked to PfART-R in southeast Asia. Seven databases were searched (PubMed, Embase, Scopus, African Journal Online, African Index Medicus, Bioline, and Web of Science) for relevant articles about polymorphisms of the Pfkelch13 gene in Africa before January, 2019.

Novel anti-malarial drug strategies to prevent artemisinin partner drug resistance: A model-based analysis

March 30, 2021 - 14:22 -- Open Access
Kunkel A, White M, Piola P
PLoS Comput Biol. 2021 Mar 25;17(3):e1008850

Emergence of resistance to artemisinin and partner drugs in the Greater Mekong Subregion has made elimination of malaria from this region a global priority; it also complicates its achievement. Novel drug strategies such as triple artemisinin combination therapies (ACTs) and chemoprophylaxis have been proposed to help limit resistance and accelerate elimination. The objective of this study was to better understand the potential impacts of triple ACTs and chemoprophylaxis, using a mathematical model parameterized using data from Cambodia.

NOT Open Access | Superoxide: A major role in the mechanism of action of essential antimalarial drugs

March 17, 2021 - 16:48 -- NOT Open Access
Egwu CO, Tsamesidis I, Pério P, Augereau JM, Benoit-Vical F, Reybier K
Free Radic Biol Med. 2021 Mar 12:S0891-5849(21)00150-7

Understanding the mode of action of antimalarials is central to optimizing their use and the discovery of new therapeutics. Currently used antimalarials belong to a limited series of chemical structures and their mechanisms of action are continually debated. Whereas the involvement of reactive species that in turn kill the parasites sensitive to oxidative stress, is accepted for artemisinins, little is known about the generation of such species in the case of quinolines or hydroxynaphtoquinone. Moreover, the nature of the reactive species involved has never been characterized in Plasmodium-infected erythrocytes.


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