Reduced Impact of Pyrimethamine Drug Pressure on Plasmodium malariae Dihydrofolate Reductase Gene Nimol Khim a , Saorin Kim a , Christiane Bouchier b , Magali Tichit b , Frédéric Ariey c , Thierry Fandeur d , Pheaktra Chim a , Sopheakvatey Ke a , Sarorn Sum a , Somnang Man a , Arsène Ratsimbasoa e , Rémy Durand f and Didier Ménard a a Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur du Cambodge, Phnom Penh, Cambodia b Génopôle de l'Ile de France, Plate-forme Génomique, Institut Pasteur, Paris, France c Unité de Parasitologie Médicale, Centre International de Recherches Médicales de Franceville, Franceville, Gabon d Centre de Recherches Médicales et Sanitaires, CERMES, Niamey, Niger e Departement de Santé Publique, Faculté de Médecine, Université d'Antananarivo, Antananarivo, Madagascar f Laboratoire de Parasitologie-Mycologie, AP-HP Hôpital Avicenne, Bobigny, France ABSTRACT Molecular investigations performed following the emergence of sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum have allowed the identification of the dihydrofolate reductase (DHFR) enzyme as the target of pyrimethamine. Although clinical cases of Plasmodium malariae are not usually treated with antifolate therapy, incorrect diagnosis and the high frequency of undetected mixed infections has probably exposed non- P. falciparum parasites to antifolate therapy in many areas. In this context, we aimed to assess the worldwide genetic diversity of the P. malariae dhfr gene in 123 samples collected in Africa and Asia, areas with different histories of SP use. Among the 10 polymorphic sites found, we have observed 7 new mutations (K55E, S58R, S59A, F168S, N194S, D207G, and T221A), which led us to describe 6 new DHFR proteins. All isolates from African countries were classified as wild type, while new mutations and haplotypes were recognized as exclusive to Madagascar (except for the double mutations at nucleotides 341 and 342 (S114N) found in one Cambodian isolate). Among these nonsynonymous mutations, two were likely related to pyrimethamine resistance: S58R (corresponding to C59R in P. falciparum and S58R in Plasmodium vivax ; observed in one Malagasy sample) and S114N (corresponding to S108N in P. falciparum and S117N in P. vivax ; observed in three Cambodian samples).
Reduced Impact of Pyrimethamine Drug Pressure on Plasmodium malariae Dihydrofolate Reductase Gene
Abstract
Reduced Impact of Pyrimethamine Drug Pressure on Plasmodium malariae Dihydrofolate Reductase Gene Nimol Khim a , Saorin Kim a , Christiane Bouchier b , Magali Tichit b , Frédéric Ariey c , Thierry Fandeur d , Pheaktra Chim a , Sopheakvatey Ke a , Sarorn Sum a , Somnang Man a , Arsène Ratsimbasoa e , Rémy Durand f and Didier Ménard a a Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur du Cambodge, Phnom Penh, Cambodia b Génopôle de l'Ile de France, Plate-forme Génomique, Institut Pasteur, Paris, France c Unité de Parasitologie Médicale, Centre International de Recherches Médicales de Franceville, Franceville, Gabon d Centre de Recherches Médicales et Sanitaires, CERMES, Niamey, Niger e Departement de Santé Publique, Faculté de Médecine, Université d'Antananarivo, Antananarivo, Madagascar f Laboratoire de Parasitologie-Mycologie, AP-HP Hôpital Avicenne, Bobigny, France ABSTRACT Molecular investigations performed following the emergence of sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum have allowed the identification of the dihydrofolate reductase (DHFR) enzyme as the target of pyrimethamine. Although clinical cases of Plasmodium malariae are not usually treated with antifolate therapy, incorrect diagnosis and the high frequency of undetected mixed infections has probably exposed non- P. falciparum parasites to antifolate therapy in many areas. In this context, we aimed to assess the worldwide genetic diversity of the P. malariae dhfr gene in 123 samples collected in Africa and Asia, areas with different histories of SP use. Among the 10 polymorphic sites found, we have observed 7 new mutations (K55E, S58R, S59A, F168S, N194S, D207G, and T221A), which led us to describe 6 new DHFR proteins. All isolates from African countries were classified as wild type, while new mutations and haplotypes were recognized as exclusive to Madagascar (except for the double mutations at nucleotides 341 and 342 (S114N) found in one Cambodian isolate). Among these nonsynonymous mutations, two were likely related to pyrimethamine resistance: S58R (corresponding to C59R in P. falciparum and S58R in Plasmodium vivax ; observed in one Malagasy sample) and S114N (corresponding to S108N in P. falciparum and S117N in P. vivax ; observed in three Cambodian samples).Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Reduced Impact of Pyrimethamine Drug Pressure on Plasmodium malariae Dihydrofolate Reductase Gene
Khim, Nimol; Kim, Saorin; Bouchier, Christiane; Tichit, Magali; Ariey, Frédéric; Fandeur, Thierry; Chim, Pheaktra; Ke, Sopheakvatey; Sum, Sarorn; Man, Somnang; Ratsimbasoa, Arsène; Durand, Rémy; Ménard, Didier
Follow Antimicrobial Agents and Chemotherapy
, Volume 56 (2): 863
American Society For Microbiology – Feb 1, 2012
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