Molecular genetic mechanisms of drug resistance in Plasmodium falciparum


DOI: https://dx.doi.org/10.18565/epidem.2020.10.4.80-7

Solovyev A.I., Uskov A.N., Kovalenko A.N., Kapatsyna V.A., Rakin A.I.

1) S.M. Kirov Military Medical Academy, Ministry of Defense of the Russian Federation, Saint Petersburg, Russia; 2) Pediatric Research and Clinical Center for Infectious Diseases, Federal Biomedical Agency of Russia, Saint Petersburg, Russia; 3) S.P. Botkin Clinical Infectious Diseases Hospital, Saint Petersburg, Russia
Objective. To investigate the metabolic characteristics of P. falciparum, the pharmacological action of antimalarial drugs, and the molecular genetic mechanisms of drug resistance in the malaria pathogen P. falciparum.
Materials and methods. Data on current antimalarial drugs, the genome of Plasmodium malaria, and the mechanisms of drug resistance in P. falciparum were analyzed.
Results. It was shown that antimalarial drugs could block or competitively replace transport proteins, and the key parasite enzymes that catalyzed the major metabolic pathways of plastic and energy exchange. The targets could be metabolites of hemoglobin absorbed by Plasmodium, enzymes involved in the electron transport chain, as well as parasite enzymes, such as cytochrome b, dihydropteroate synthase, dihydrofolate reductase, calcium-dependent ATP synthase, phosphatidylinositol-3-hydrogen kinase, dihydroorotate dehydrogenase, and others. The main mechanisms of drug resistance were associated with the genetic heterogeneity of infectious agents. Of great importance in the formation of resistance are SNP mutations at the loci of the PfCRT, PfMDR1, PfATP6, PfDHPS, PfDHFR, and PfCYTB genes, as well as genetic recombination in Plasmodium during erythrocytic schizogony. The formation of resistant strains and the selection of drug resistance mutations were facilitated by long-term blood parasite persistence while taking antimalarial drugs.
Conclusion. The basic principles of etiotropic treatment for malaria should be early treatment, as well as combination therapy using the most effective antimalarial drugs of different pharmacological groups at dosages ensuring the rapid elimination of pathogens from the patient’s body.
Keywords: PfCRT, PfCYTB, PfDHFR, PfDHPS, PfATP6, PfMDR1, malaria, P. falciparum, drug resistance, genome
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About the Autors

Aleksey I. Solovуev, MD, Professor, Department of Biology (with Course of Medical Genetics), S.M. Kirov Military Medical Academy, Ministry of Defense of the Russian Federation, Saint Petersburg, Russia; email: solopiter@gmail.com; ORCID: https://orcid.org/0000-0002-3731-1756
Aleksandr N. Uskov, MD, Professor, Deputy Director for Research in the Development and Coordination of National and International Projects, Pediatric Research and Clinical Center for Infectious Diseases, Federal Biomedical Agency, Saint Petersburg, Russia, email: aouskov@gmail.com; ORCID: https://orcid. org/0000-0003-3185-516X
Aleksandr N. Kovalenko, MD, Associate Professor, Department of Infectious Diseases (with Course of Medical Parasitology and Tropical Diseases), S.M. Kirov Military Medical Academy, Ministry of Defense of the Russian Federation, Saint Petersburg, Russia, email: 9268754@mail.ru; ORCID: //orcid.org/0000-0002-2976-8051
Vladimir A. Kapatsyna, Head, Department, S.P. Botkin Clinical Infectious Diseases Hospital, Saint Petersburg, Russia, email: ingashi@mail.ru; ORCID: https://orcid.org/0000-0002-2976-8051
Aleksandr I. Rakin, Educator, Department of Biology (with Course of Medical Genetics), S.M. Kirov Military Medical Academy, Ministry of Defense of the Russian Federation, Saint Petersburg, Russia; email: rakinalex@gmail.com; ORCID: https://orcid.org/0000-0001-9085-1287


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