Plasmodium falciparum resistance to artemisinin-based combination therapies

Ward, Kurt E.; Fidock, David A.; Bridgford, Jessica L.

doi:10.1016/j.mib.2022.102193

Cited by 34 publications

(27 citation statements)

References 83 publications

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“…Single-point mutations in Kelch13 (K13) have been identified as the primary mediator of ART resistance in asexual blood stage (ABS) P. falciparum parasites (9)(10)(11)(12). Mechanistically, K13 mutations are thought to reduce endocytosis of host hemoglobin, effectively lowering ART activation by hemoglobin-derived heme (13)(14)(15), thus attenuating drug-mediated redox perturbations, protein alkylation, and proteotoxic stress (16)(17)(18). Worryingly, mutant K13 variants have now emerged independently in Rwanda and Uganda, with evidence of delayed parasite clearance as well as increased survival of DHA-treated ring-stage parasites (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Mok,

Yeo,

Hong

et al. 2023

Sci. Adv.

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Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

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Section: Introductionmentioning

confidence: 99%

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Mok,

Yeo,

Hong

et al. 2023

Sci. Adv.

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“…Resistant strains are designated as P. falciparum chloroquine resistance transporter ( PfCRT ) gene, ABC transporter P. falciparum multidrug resistance ( PfMDR1 ) gene and altered chloroquine-transporter protein, CG2 has been associated with chloroquine resistance. Subsequently, a treatment combination of chloroquine with other drug agents has been proposed to avoid this resistance [ 8 , 9 ].…”

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confidence: 99%

The Next Generation of Malaria Treatments: The Great Expectations

Abumsimir

Al-Qaisi

2023

Future Sci. OA

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“…P. falciparum is the species with which most of the malaria disease burden is associated, and of great concern is the emergence of parasite resistance to frontline artemisinin combination therapies (ACTs) around the globe. − This expanding antimalarial resistance highlights an urgent need to discover and develop novel antimalarial medicines that have different mechanisms of action (MoA) from those currently in use, most of which parasites have developed some degree of resistance to. To date, efforts to develop new antimalarials have largely centered on performing phenotypic screens of compound libraries for small molecules that inhibit the growth of the disease-causing asexual blood stage of P.…”

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confidence: 99%

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

Ling,

Nguyen,

Looker

et al. 2023

ACS Infect. Dis.

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With the resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany, of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250 was prioritized for further optimization. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound, MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting that this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite's life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB that clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies that showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.

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Plasmodium falciparum resistance to artemisinin-based combination therapies

Cited by 34 publications

References 83 publications

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

The Next Generation of Malaria Treatments: The Great Expectations

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite’s PI4KIIIB Enzyme

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