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Antimicrobial Agents and Chemotherapy, April 2009, p. 1362-1366, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01656-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Known Molecular Markers of Resistance in the Antimalarial Potency of Piperaquine and Dihydroartemisinin In Vitro{triangledown}

Sant Muangnoicharoen,1 David J. Johnson,1 Sornchai Looareesuwan,2 Srivicha Krudsood,2 and Stephen A. Ward1*

Molecular and Biochemical Parasitology Group, Centre for Tropical and Infectious Diseases, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom,1 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand2

Received 17 December 2008/ Returned for modification 14 January 2009/ Accepted 22 January 2009

Using a range of laboratory-adapted and genetically modified Plasmodium falciparum parasite isolates, we investigated the interaction between dihydroartemisinin and piperaquine (PIP), the individual components of an artemisinin combination therapy currently under development, in addition to the role of known drug resistance genes in parasite susceptibility in vitro. All but one parasite line investigated displayed an interaction of dihydroartemisinin and PIP that was antagonistic, although the degree of antagonism was isolate dependent. In terms of resistance markers, the pfcrt haplotypes CVIET and SVMNT were positively associated with reduced sensitivity to PIP, with parasites carrying the South American CQR (SVMNT) allele being generally less sensitive than CVIET parasites. Parasites carrying the CQS (CVMNK) allele displayed a further increase in PIP sensitivity compared with CVIET and SVMNT parasites. Our data indicate that PIP sensitivity was not affected by pfmdr1 sequence status, despite positive correlations between the structurally related compound amodiaquine and pfmdr1 mutations in other studies. In contrast, neither the pfcrt nor pfmdr1 sequence status had any significant impact on susceptibility to dihydroartemisinin.

* Corresponding author. Mailing address: Molecular and Biochemical Parasitology Group, Centre for Tropical and Infectious Diseases, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom. Phone: 44 151 705 3286. Fax: 44 151 705 3371. E-mail: saward{at}liv.ac.uk

{triangledown} Published ahead of print on 2 February 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1362-1366, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01656-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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