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Handbook of Antimicrobial Resistance pp 289–311Cite as

The Biochemistry of Quinoline Antimalarial Drug Resistance

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Abstract

Mutations in the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) have been shown to be central to the molecular mechanism of quinoline antimalarial drug resistance. However, additional facets to resistance biochemistry are emerging, and it is now clear that multiple quinoline drug resistance phenotypes exist in different regions of the globe. Different public health policies and drug use histories across the globe, along with natural genetic drift, have created this diversity, such that there are now dozens of distinct chloroquine-resistant (CQR) strains of P. falciparum. Some of these can be described in detail, but information is incomplete. This leads to some degree of continued uncertainty on how best to proceed in controlling malaria in some regions. This issue is even more critical for controlling chloroquine-resistant P. vivax, about which even less is known. This review summarizes key features of quinoline antimalarial drug resistance in P. falciparum malaria and suggests concepts relevant for “staying ahead of the resistance curve.”

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Abbreviations

ABC:

ATP-binding cassette

ACT:

Artemisinin combination therapy

ATP:

Adenosine triphosphate

CQ:

Chloroquine

CQR:

CQ resistant (resistance)

CQS:

CQ sensitive

DV:

Digestive vacuole

FPIX:

Ferriprotoporphyrin IX

Hb:

Hemoglobin

HF:

Halofantrine

Hz:

Hemozoin

iRBC:

Red blood cell infected with P. falciparum

ISOV:

Inside–out yeast plasma membrane vesicle

MDR:

Multidrug resistant (resistance)

MQ:

Mefloquine

pfcrt/PfCRT:

Plasmodium falciparum chloroquine-resistance transporter (gene/PROTEIN)

PfMDR1:

P. falciparum multidrug resistance protein 1

PfNHE:

P. falciparum Na+/H+ exchanger

pvs:

Parasitophorous vacuolar space

QD:

Quinidine

QN:

Quinine

QNR:

Quinine resistance

QTL:

Quantitative trait loci

RBC:

Red blood cell

VPL:

Verapamil

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Acknowledgments

Many outstanding laboratory colleagues have contributed to the studies from the Roepe laboratory mentioned in this chapter. We thank in particular Drs. L. Ursos, S. Dzekunov, E. Howard, T. Bennett, B. Gligorejevic, A. Kosar, L. Amoah, J. Lekostaj, M. Paguio, M. Cabrera, C. Xie, J. Alumasa, N. Baro, A. Gorka, and D. Gaviria. We also thank A. Siriwardana, Y. Liu, K. Sherlach, L. Jacobs, L. Turnbull, Drs. A. Sinai and M. Ferdig for additional helpful discussions, and Dr. A. Gorka for helping with Fig. 1. The work done in the Roepe laboratory since the cloning of pfcrt has been supported by the Burroughs Wellcome Foundation, the Luce Foundation, the US Department of Defense, and the NIH (RO1 AI045957, AI056312, AI052312, AI060792, and AI071121).

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  1. Department of Chemistry, Department of Biochemistry, Cellular and Molecular Biology, and Center for Infectious Disease, Georgetown University, 37th and O Streets, Washington, DC, 20057, USA

    Paul S. Callaghan & Paul D. Roepe

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Correspondence to Paul D. Roepe .

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Editors and Affiliations

  1. Department of Microbiology and Immunology, McGill University, Montreal, Québec, Canada

    Albert Berghuis

  2. Department of Microbiology and Immunology, McGill University, Montreal, Québec, Canada

    Greg Matlashewski

  3. Department of Microbiology and Immunology, McGill University, Montreal, Québec, Canada

    Mark A. Wainberg

  4. Department of Microbiology and Immunology, McGill University, Montreal, Québec, Canada

    Donald Sheppard

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© 2017 Springer Science+Business Media New York

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Callaghan, P.S., Roepe, P.D. (2017). The Biochemistry of Quinoline Antimalarial Drug Resistance. In: Berghuis, A., Matlashewski, G., Wainberg, M., Sheppard, D. (eds) Handbook of Antimicrobial Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0694-9_16

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