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Antimicrobial Agents and Chemotherapy, June 2004, p. 2214-2222, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2214-2222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sulfadoxine Resistance in Plasmodium vivax Is Associated with a Specific Amino Acid in Dihydropteroate Synthase at the Putative Sulfadoxine-Binding Site

Michael Korsinczky,1,2,{dagger} Katja Fischer,3,{dagger} Nanhua Chen,1 Joanne Baker,1 Karl Rieckmann,1 and Qin Cheng1*

Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, Qld 4051,1 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Qld 4067,2 Malaria and Scabies Group, The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Qld 4029, Australia3

Received 22 October 2003/ Returned for modification 26 November 2003/ Accepted 24 February 2004

Sulfadoxine is predominantly used in combination with pyrimethamine, commonly known as Fansidar, for the treatment of Plasmodium falciparum. This combination is usually less effective against Plasmodium vivax, probably due to the innate refractoriness of parasites to the sulfadoxine component. To investigate this mechanism of resistance by P. vivax to sulfadoxine, we cloned and sequenced the P. vivax dhps (pvdhps) gene. The protein sequence was determined, and three-dimensional homology models of dihydropteroate synthase (DHPS) from P. vivax as well as P. falciparum were created. The docking of sulfadoxine to the two DHPS models allowed us to compare contact residues in the putative sulfadoxine-binding site in both species. The predicted sulfadoxine-binding sites between the species differ by one residue, V585 in P. vivax, equivalent to A613 in P. falciparum. V585 in P. vivax is predicted by energy minimization to cause a reduction in binding of sulfadoxine to DHPS in P. vivax compared to P. falciparum. Sequencing dhps genes from a limited set of geographically different P. vivax isolates revealed that V585 was present in all of the samples, suggesting that V585 may be responsible for innate resistance of P. vivax to sulfadoxine. Additionally, amino acid mutations were observed in some P. vivax isolates in positions known to cause resistance in P. falciparum, suggesting that, as in P. falciparum, these mutations are responsible for acquired increases in resistance of P. vivax to sulfadoxine.

* Corresponding author. Mailing address: Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, Qld 4051, Australia. Phone: 61-7-3332 4834. Fax: 61-7-3332 4800. E-mail: qin.cheng{at}defence.gov.au.

{dagger} These authors contributed equally.

Antimicrobial Agents and Chemotherapy, June 2004, p. 2214-2222, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2214-2222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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