Artemisinin resistance, some facts and opinions

Pantaleo, Antonella; Pau, Maria Carmina; Chien, Huynh Dinh; Turrini, Francesco Michelangelo

doi:10.3855/jidc.7015

Cited by 5 publications

(5 citation statements)

References 17 publications

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“…On the other hand, the co-occurrence of ART resistance and resistance to the partner drugs was described to be associated to high rates of clinical treatment failure [23,26]. In addition, the available ART resistance markers are affected by some technical limitations: i) their sensitivity and specificity are still undefined [27]; ii) resistance to mefloquine and piperaquine is, by itself, a demonstrated cause of clinical treatment failure of ACTs but the absence of a genetic marker cannot exclude drug resistance; iii) the rate of clearance of parasitized erythrocytes is multi-factorial being influenced by resistance to anti-malarial drugs and host factors, such as immunity and mutations affecting erythrocyte viability (G6PD deficiency and thalassemias) that may vary in the different areas.…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam

et al. 2019

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Background In Vietnam, a rapid decline of P . falciparum malaria cases has been documented in the past years, the number of Plasmodium falciparum malaria cases has rapidly decreased passing from 19.638 in 2012 to 4.073 cases in 2016. Concomitantly, the spread of artemisinin resistance markers is raising concern on the future efficacy of the ACTs. An evaluation of the clinical impact of the artemisinin resistance markers is therefore of interest. Methods The clinical effectiveness of dihydroartemisinin-piperaquine therapy (DHA-PPQ) has been evaluated in three districts characterized by different rates of ART resistance markers: K13(C580Y) mutation and delayed parasite clearance on day 3 (DPC3). Patients were stratified in 3 groups a) no markers, b) one marker (suspected resistance), c) co-presence of both markers (confirmed resistance). In the studied areas, the clinical effectiveness of DHA-PPQ has been estimated as malaria recrudescence within 60 days. Results The rate of K13(C580Y) ranged from 75.8% in Krong Pa to 1.2% in Huong Hoa district. DPC3 prevalence was higher in Krong Pa than in Huong Hoa (86.2% vs 39.3%). In the two districts, the prevalence of confirmed resistance was found in 69.0% and 1.2% of patients, respectively. In Thuan Bac district, we found intermediate prevalence of confirmed resistance. Treatment failure was not evidenced in any district. PPQ resistance was not evidenced. Confirmed resistance was associated to the persistence of parasites on day 28 and to 3.4-fold higher parasite density at diagnosis. The effectiveness of malaria control strategies was very high in the studied districts. Conclusion No treatment failure has been observed in presence of high prevalence of ART resistance and in absence of PPQ resistance. K13(C580Y) was strongly associated to higher parasitemia at admission, on days 3 and 28. Slower parasite clearance was also observed in younger patients.

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Section: Introductionmentioning

confidence: 99%

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam

et al. 2019

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“…For instance, chloroquine-resistant P. falciparum has spread to most malaria-manifested areas up to date. Even for the most effective antimalarial drug artemisinin, its resistance was first reported in 2008, which has become a major issue in parts of Southeast Asia. ,− To tackle these important problems, there is an urgent requirement for new antimalarial drugs.…”

Section: Introductionmentioning

confidence: 99%

Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

Yang

et al. 2017

J. Med. Chem.

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Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.

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“…1,2 Because strains of P falciparum are rapidly emerging that are resistant to all known antimalarial drugs, including artemisinin, quinine, chloroquine, piperaquine, and mefloquine and their derivatives, considerable emphasis is now being focused on development of new therapies with novel mechanisms of action. [2][3][4][5][6] Although reports of promising new antimalarials are now appearing in the literature, [7][8][9][10][11][12][13][14][15] that vast majority of these novel drug candidates target parasite-encoded proteins/pathways, leaving the opportunity open for adventitious parasites to mutate resistance to the new therapeutics. As noted by others, the ideal solution to this problem would emerge if new antimalarials could be developed that would function by inhibiting a hostencoded protein/pathway that the parasite must coopt in order to survive and proliferate.…”

Section: Introductionmentioning

confidence: 99%

Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress

Pantaleo

Kesely

Pau

et al. 2017

Blood

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Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of 's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasite-induced band 3 tyrosine phosphorylation and inhibit parasite-promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance.

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Artemisinin resistance, some facts and opinions

Cited by 5 publications

References 17 publications

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam

Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress

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