HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gregson, A. Articles by Plowe, C. V. Search for Related Content PubMed PubMed Citation Articles by Gregson, A. Articles by Plowe, C. V.

Article

Mechanisms of Resistance of Malaria Parasites to Antifolates

Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland

Abstract

I. Introduction

A. Life Cycle of Plasmodium falciparum

B. Folate Biosynthesis in Plasmodia

II. Malaria Parasite Drug Resistance

A. Historical Perspective

1. Chloroquine.

2. Synthetic Antimalarials.

3. Proguanil.

4. Pyrimethamine.

5. Sulfa Drugs.

6. Combined Dihydrofolate Reductase Inhibitors and Sulfonamide Drugs.

7. Aryl Amino Alcohols.

8. General Concepts Learned from Early Experiences.

B. Antifolates and Nonfalciparum Malaria

C. Drug Effects on Parasite Stages

D. Parasite Clearance Following Antimalarial Drug Treatment

III. Dihydrofolate Reductase-Thymidylate Synthase

A. Dihydrofolate Reductase Inhibitors

1. Cross-Resistance between Dihydrofolate Reductase Inhibitors.

B. Identification of Antifolate Drug Target

C. Point Mutations within Dihydrofolate Reductase Are Responsible for in Vitro Resistance

D. The Move to Field Isolates

E. Gene Amplification

F. Mutation Rates within the Dihydrofolate Reductase Gene

G. Enzyme Kinetic Analysis of Dihydrofolate Reductase

H. Relationship of Point Mutations to Dihydrofolate Reductase Structure—Crystallography

IV. Pyrophosphokinase-Dihydropteroate Synthase

A. Folate Effect

1. Folate Effect and Drug Resistance.

2. Folate Effect and in Vitro Sulfonamide Testing.

B. Markers of in Vitro Resistance in Dihydropteroate Synthase

C. Enzyme Kinetics Studies on Dihydropteroate Synthase

D. Relationship of Point Mutations to Dihydropteroate Synthase Structure—Crystallography

V. Parasitologic Resistance Does Not Equal Clinical Failure

A. In Vivo Drug Failure, Additional Host Factors

1. In Vivo Folate Effect.

B. Molecular Markers and Treatment Outcomes

VI. Molecular Assays

VII. Molecular Epidemiological Studies

A. Drug Treatment Effect on Post-Treatment Parasite Genotype

B. Molecular Markers and Treatment Outcomes

1. High Endemicity.

2. Low Endemicity.

C. Worldwide Distribution of Dihydrofolate Reductase and Dihydropteroate Synthase Mutations

D. Molecular Markers and Treatment Outcome—Summary

VIII. Using Genotype to Predict Clinical Failure

IX. Other Antifolates

A. Trimethoprim-Sulfamethoxazole

B. Chlorproguanil-Dapsone

X. New Directions—Drug Development

A. The ''Old'' Combinations

B. New Directions—Combination Drug Therapy

XI. Summary

Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.

This article has been cited by other articles:

				A. M. McCollum, L. K. Basco, R. Tahar, V. Udhayakumar, and A. A. Escalante Hitchhiking and Selective Sweeps of Plasmodium falciparum Sulfadoxine and Pyrimethamine Resistance Alleles in a Population from Central Africa Antimicrob. Agents Chemother., November 1, 2008; 52(11): 4089 - 4097. [Abstract] [Full Text] [PDF]

				M. F. Boni, D. L. Smith, and R. Laxminarayan Benefits of using multiple first-line therapies against malaria PNAS, September 16, 2008; 105(37): 14216 - 14221. [Abstract] [Full Text] [PDF]

				G. Q. Zhang, Y. Y. Guan, H. H. Sheng, B. Zheng, S. Wu, H. S. Xiao, and L. H. Tang Multiplex PCR and Oligonucleotide Microarray for Detection of Single-Nucleotide Polymorphisms Associated with Plasmodium falciparum Drug Resistance J. Clin. Microbiol., July 1, 2008; 46(7): 2167 - 2174. [Abstract] [Full Text] [PDF]

				D. Plouffe, A. Brinker, C. McNamara, K. Henson, N. Kato, K. Kuhen, A. Nagle, F. Adrian, J. T. Matzen, P. Anderson, et al. From the Cover: In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen PNAS, July 1, 2008; 105(26): 9059 - 9064. [Abstract] [Full Text] [PDF]

				K. Rungsihirunrat, C. H. Sibley, M. Mungthin, and K. Na-Bangchang Geographical Distribution of Amino Acid Mutations in Plasmodium vivax DHFR and DHPS from Malaria Endemic Areas of Thailand Am J Trop Med Hyg, March 1, 2008; 78(3): 462 - 467. [Abstract] [Full Text] [PDF]

				A. Cavazzuti, G. Paglietti, W. N. Hunter, F. Gamarro, S. Piras, M. Loriga, S. Allecca, P. Corona, K. McLuskey, L. Tulloch, et al. Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development PNAS, February 5, 2008; 105(5): 1448 - 1453. [Abstract] [Full Text] [PDF]

				Z. Zhou, S. M. Griffing, A. M. de Oliveira, A. M. McCollum, W. M. Quezada, N. Arrospide, A. A. Escalante, and V. Udhayakumar Decline in Sulfadoxine-Pyrimethamine-Resistant Alleles after Change in Drug Policy in the Amazon Region of Peru Antimicrob. Agents Chemother., February 1, 2008; 52(2): 739 - 741. [Abstract] [Full Text] [PDF]

				M. D. Edstein, B. M. Kotecka, A. L. Ager, K. S. Smith, C. A. DiTusa, D. S. Diaz, D. E. Kyle, G. A. Schiehser, D. P. Jacobus, K. H. Rieckmann, et al. Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate JPC2056 in cynomolgus monkeys using an in vivo in vitro model J. Antimicrob. Chemother., October 1, 2007; 60(4): 811 - 818. [Abstract] [Full Text] [PDF]

				A. M. McCollum, K. Mueller, L. Villegas, V. Udhayakumar, and A. A. Escalante Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America Antimicrob. Agents Chemother., June 1, 2007; 51(6): 2085 - 2091. [Abstract] [Full Text] [PDF]

				K. RUNGSIHIRUNRAT, K. NA-BANGCHANG, V. N. HAWKINS, M. MUNGTHIN, and C. H. SIBLEY SENSITIVITY TO ANTIFOLATES AND GENETIC ANALYSIS OF PLASMODIUM VIVAX ISOLATES FROM THAILAND Am J Trop Med Hyg, June 1, 2007; 76(6): 1057 - 1065. [Abstract] [Full Text] [PDF]

				M. T. Alam, H. Bora, P. K. Bharti, M. A. Saifi, M. K. Das, V. Dev, A. Kumar, N. Singh, A. P. Dash, B. Das, et al. Similar Trends of Pyrimethamine Resistance-Associated Mutations in Plasmodium vivax and P. falciparum Antimicrob. Agents Chemother., March 1, 2007; 51(3): 857 - 863. [Abstract] [Full Text] [PDF]

				Z. Zhou, A. C. Poe, J. Limor, K. K. Grady, I. Goldman, A. M. McCollum, A. A. Escalante, J. W. Barnwell, and V. Udhayakumar Pyrosequencing, a High-Throughput Method for Detecting Single Nucleotide Polymorphisms in the Dihydrofolate Reductase and Dihydropteroate Synthetase Genes of Plasmodium falciparum J. Clin. Microbiol., November 1, 2006; 44(11): 3900 - 3910. [Abstract] [Full Text] [PDF]

				A. Ahmed, V. Lumb, M. K. Das, V. Dev, Wajihullah, and Y. D. Sharma Prevalence of Mutations Associated with Higher Levels of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum Isolates from Car Nicobar Island and Assam, India Antimicrob. Agents Chemother., November 1, 2006; 50(11): 3934 - 3938. [Abstract] [Full Text] [PDF]

				A. Nzila The past, present and future of antifolates in the treatment of Plasmodium falciparum infection J. Antimicrob. Chemother., June 1, 2006; 57(6): 1043 - 1054. [Abstract] [Full Text] [PDF]

				A. Ahmed, M. K. Das, V. Dev, M. A. Saifi, Wajihullah, and Y. D. Sharma Quadruple Mutations in Dihydrofolate Reductase of Plasmodium falciparum Isolates from Car Nicobar Island, India. Antimicrob. Agents Chemother., April 1, 2006; 50(4): 1546 - 1549. [Abstract] [Full Text] [PDF]

				M. Llinas, Z. Bozdech, E. D. Wong, A. T. Adai, and J. L. DeRisi Comparative whole genome transcriptome analysis of three Plasmodium falciparum strains Nucleic Acids Res., February 21, 2006; 34(4): 1166 - 1173. [Abstract] [Full Text] [PDF]

				H. C. HAPUARACHCHI, M. Y. D. DAYANATH, K. B. A. T. BANDARA, S. ABEYSUNDARA, W. ABEYEWICKREME, N. R. DE SILVA, S. Y. HUNT, and C. H. SIBLEY POINT MUTATIONS IN THE DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENES OF PLASMODIUM FALCIPARUM AND RESISTANCE TO SULFADOXINE-PYRIMETHAMINE IN SRI LANKA Am J Trop Med Hyg, February 1, 2006; 74(2): 198 - 204. [Abstract] [Full Text] [PDF]

				N. Khim, C. Bouchier, M.-T. Ekala, S. Incardona, P. Lim, E. Legrand, R. Jambou, S. Doung, O. M. Puijalon, and T. Fandeur Countrywide Survey Shows Very High Prevalence of Plasmodium falciparum Multilocus Resistance Genotypes in Cambodia Antimicrob. Agents Chemother., August 1, 2005; 49(8): 3147 - 3152. [Abstract] [Full Text] [PDF]