Amodiaquine Resistance in Plasmodium Berghei is Associated with Pbcrt His95Pro Mutation, Loss of Chloroquine, Artemisinin and Primaquine Sensitivity, and High Transcript Levels of Key Transporters [Version 2; Referees: 3 Approved]

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dc.contributor.author Ndung'u, L.
dc.contributor.author Langat, B.
dc.contributor.author Magiri, E.
dc.contributor.author Ng'ang'a, J.
dc.contributor.author Irungu, B.
dc.contributor.author Nzila, A.
dc.contributor.author Kiboi, D.
dc.date.accessioned 2019-07-29T12:34:45Z
dc.date.available 2019-07-29T12:34:45Z
dc.date.issued 2018-06
dc.identifier.other Vol.2(14)
dc.identifier.other doi: 10.12688/wellcomeopenres.11768.1
dc.identifier.uri http://ugspace.ug.edu.gh/handle/123456789/31858
dc.description.abstract Background: The human malaria parasite Plasmodium falciparum has evolved drug evasion mechanisms to all available antimalarials. The combination of amodiaquine-artesunate is among the drug of choice for treatment of uncomplicated malaria. In this combination, a short-acting, artesunate is partnered with long-acting, amodiaquine for which resistance may emerge rapidly especially in high transmission settings. Here, we used a rodent malaria parasite Plasmodium berghei ANKA as a surrogate of P. falciparum to investigate the mechanisms of amodiaquine resistance. Methods: We used the ramp up approach to select amodiaquine resistance. We then employed the 4-Day Suppressive Test to measure the resistance level and determine the cross-resistance profiles. Finally, we genotyped the resistant parasite by PCR amplification, sequencing and relative quantitation of mRNA transcript of targeted genes. Results: Submission of the parasite to amodiaquine pressure yielded resistant line within thirty-six passages. The effective doses that reduced 90% of parasitaemia (ED 90) of the sensitive and resistant lines were 4.29mg/kg and 19.13mg/kg respectively. The selected parasite retained resistance after ten passage cycles in the absence of the drug and freezing at -80ºC for one month with ED 90 of 20.34mg/kg and 18.22mg/kg. The parasite lost susceptibility to chloroquine by (6-fold), artemether (10-fold), primaquine (5-fold), piperaquine (2-fold) and lumefantrine (3-fold). Sequence analysis of Plasmodium berghei chloroquine-resistant transporter revealed His95Pro mutation. We found no variation in the nucleotide sequences of Plasmodium berghei multidrug resistance gene-1 (Pbmdr1), Plasmodium berghei deubiquitinating enzyme-1 or Plasmodium berghei Kelch13 domain. However, high mRNA transcripts of essential transporters; Pbmdr1, V-type/H+ pumping pyrophosphatase-2 and sodium hydrogen ion exchanger-1 and Ca 2+/H + antiporter accompanies amodiaquine resistance. Conclusions: The selection of amodiaquine resistance yielded stable “multidrug-resistant’’ parasites and thus may be used to study shared resistance mechanisms associated with other antimalarial drugs. Genome-wide analysis of the parasite may elucidate other functionally relevant genes controlling AQ resistance in P. berghei. en_US
dc.language.iso en en_US
dc.publisher Wellcome Open Research en_US
dc.subject Malaria en_US
dc.subject Resistance en_US
dc.subject Plasmodium Berghei en_US
dc.subject Amodiaquine en_US
dc.subject Cross-Resistance en_US
dc.title Amodiaquine Resistance in Plasmodium Berghei is Associated with Pbcrt His95Pro Mutation, Loss of Chloroquine, Artemisinin and Primaquine Sensitivity, and High Transcript Levels of Key Transporters [Version 2; Referees: 3 Approved] en_US
dc.type Article en_US


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