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resistance

Not Open Access | A 6.5kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy

September 29, 2020 - 13:15 -- NOT Open Access
Author(s): 
Mugenzi LMJ, Menze BD, Wondji CS, et al.
Reference: 
Mol Ecol. 2020 Sep 24

Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions. Here, we deciphered the role of a 6.5kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector, Anopheles funestus. Whole-genome pooled sequencing detected an intergenic 6.5kb SV between duplicated CYP6P9a/b P450s in pyrethroid-resistant mosquitoes through a translocation event.

NOT Open Access | Resistance to some, but not other dimeric lindenane sesquiterpenoid esters is mediated by mutations in a Plasmodium falciparum esterase

September 29, 2020 - 13:08 -- NOT Open Access
Author(s): 
Butler JH, Baptista RP, Valenciano AL, Zhou B, Kissinger JC, Tumwebaze PK, Rosenthal PJ, Cooper R, Yue JM, Cassera MB
Reference: 
ACS Infect Dis. 2020 Sep 24

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored.

Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

September 24, 2020 - 14:02 -- Open Access
Author(s): 
Harding CR, Sidik SM, Petrova B, Gnädig NF, Okombo J, Herneisen AL, Ward KE, Markus BM, Boydston EA, Fidock DA, Lourido S
Reference: 
Nat Commun. 2020 Sep 23;11(1):4813.

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations.

NOT Open Access | Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice

September 23, 2020 - 09:36 -- NOT Open Access
Author(s): 
Wang W, Yao J, Chen Z, Sun Y, Shi Y, Wei Y, Zhou H, Yu Y, Li S, Duan L
Reference: 
Br J Pharmacol. 2020 Sep 22

Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.

Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage

September 15, 2020 - 10:59 -- Open Access
Author(s): 
Hojo-Souza NS, de Azevedo PO, de Castro JT, Teixeira-Carvalho A, Lieberman J, Junqueira C, Gazzinelli RT
Reference: 
PLoS Pathog. 2020 Sep 10;16(9):e1008840

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics.

Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

September 12, 2020 - 14:54 -- Open Access
Author(s): 
Zhou X, Zijlstra SN, Soto-Gamez A, Setroikromo R, Quax WJ
Reference: 
Cancers (Basel). 2020 Sep 4;12(9):E2514

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART).

Driving antimalarial design through understanding of target mechanism

September 2, 2020 - 08:35 -- Open Access
Author(s): 
Calic PPS, Mansouri M, Scammells PJ, McGowan S
Reference: 
Biochem Soc Trans. 2020 Sep 1:BST20200224

Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered.

NOT Open Access | Introduction of scaffold nitrogen atoms renders inhibitors of the malarial L-lactate transporter, PfFNT, effective against the Gly107Ser resistance mutation

August 24, 2020 - 13:19 -- NOT Open Access
Author(s): 
Walloch P, Henke B, Häuer S, Bergmann B, Spielmann T, Beitz E
Reference: 
J Med Chem. 2020 Aug 20

The spreading of malaria parasites, Plasmodium falciparum, with resistance to all known drugs calls for novel classes of inhibitors with new modes of action. Recently, we discovered and validated the plasmodial L-lactate transporter, PfFNT, as a novel antimalarial drug target. However, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839, gave rise to a PfFNT Gly107Ser resistance mutation decreasing inhibitor affinity by two orders of magnitude.

Aminoquinolines affording resistance to cerebral malaria of susceptible mice

August 19, 2020 - 16:05 -- Open Access
Author(s): 
Srbljanović J, Bobić B, Štajner T, Uzelac A, Opsenica I, Terzić-Jovanović N, Bauman N, Šolaja BA, Djurković-Djaković O
Reference: 
J Glob Antimicrob Resist. 2020 Aug 15:S2213-7165(20)30202-2

Malaria treatment is impeded by growing resistance to conventional drugs. We here explore the activity of 10 novel benzothiophene, thiophene and benzene aminoquinolines.

NOT Open Access | Analysis of sulphadoxine-pyrimethamine resistance-associated mutations in Plasmodium falciparum isolates obtained from asymptomatic pregnant women in Ogun State, Southwest Nigeria

August 19, 2020 - 09:17 -- NOT Open Access
Author(s): 
Fagbemi KA, Adebusuyi SA, Nderu D, Adedokun SA, Pallerla SR, Amoo AOJ, Thomas BN, Velavan TP, Ojurongbe O
Reference: 
Infect Genet Evol. 2020 Aug 14:104503

Intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) is one of the main strategies for protecting pregnant women, fetus, and their new-born against adverse effects of P. falciparum infection. The development of the drug resistance linked to mutations in P. falciparum dihydrofolate reductase gene (pfdhfr) and P. falciparum dihydropteroate synthase gene (pfdhps), is currently threatening the IPTp-SP approach.

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