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Antimicrobial Agents and Chemotherapy, November 2003, p. 3500-3505, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3500-3505.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

pfcrt Allelic Types with Two Novel Amino Acid Mutations in Chloroquine-Resistant Plasmodium falciparum Isolates from the Philippines

Nanhua Chen,1 Dennis E. Kyle,1,2 Cielo Pasay,3,{dagger} Elizabeth V. Fowler,4 Joanne Baker,1 Jennifer M. Peters,4 and Qin Cheng1*

Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Enoggera,1 Malaria and Scabies Group, Infectious Diseases Unit, Queensland Institute of Medical Research, Herston, Queensland, Australia,4 Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland,2 Department of Parasitology, The Research Institute for Tropical Medicine, Manila, Philippines3

Received 17 June 2003/ Returned for modification 22 July 2003/ Accepted 28 July 2003

Mutations in the pfcrt and pfmdr1 genes have been associated with chloroquine resistance in Plasmodium falciparum. Ten and five mutations, respectively, have been identified in these genes from chloroquine-resistant parasites worldwide. Mutation patterns in pfcrt revealed that chloroquine resistance evolved independently in southeast Asia, South America, and Papua New Guinea. However, the evolution of chloroquine resistance in the rest of the Pacific region is unclear. In this study, we examined sequence polymorphisms in these genes in isolates from Morong, Philippines, and compared them to known chloroquine resistance sequences. Two novel mutations, A144T and L160Y, were identified outside of the 10 known mutations in pfcrt in Morong isolates. These novel mutations were identified only in parasites with K76T and N326D but without the common A220S mutation found in most chloroquine-resistant isolates. This represents a unique chloroquine resistance allelic type (K76T/A144T/L160Y/N326D) not previously found elsewhere in the world. One Morong isolate also had an additional C72S mutation, whereas only one isolate possessed an allelic type typical of chloroquine resistance in Asia. Parasites with the novel pfcrt allelic types were resistant to chloroquine in vitro and were unresponsive to verapamil (0.9 µM) chemosensitization, similar to chloroquine-resistant parasites from South America and Papua New Guinea. These results suggest that chloroquine resistance evolved independently in the Philippines and represents a second chloroquine resistance founder event in the South Pacific.

* Corresponding author. Mailing address: Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Weary Dunlop Drive, 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} Present address: Infectious Diseases Unit, Queensland Institute of Medical Research, Herston, Queensland, Australia.

Antimicrobial Agents and Chemotherapy, November 2003, p. 3500-3505, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3500-3505.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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