Molecular genetic mechanisms of drug resistance in Plasmodium falciparum


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Abstract

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, PfMDRl, 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.

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About the authors

Aleksey I. Solovyev

S.M. Kirov Military Medical Academy Ministry of Defense of the Russian Federation

Email: solopiter@gmail.com
MD, Professor, Department of Biology (with Course of Medical Genetics) Saint Petersburg, Russia

Aleksandr N. Uskov

S.M. Kirov Military Medical Academy Ministry of Defense of the Russian Federation; Pediatric Research and Clinical Center for Infectious Diseases Federal Biomedical Agency of Russia

Email: aouskov@gmail.com
MD, Professor, Deputy Director for Research in the Development and Coordination of National and International Projects Saint Petersburg, Russia; Saint Petersburg, Russia

Aleksandr N. Kovalenko

S.M. Kirov Military Medical Academy Ministry of Defense of the Russian Federation

Email: 9268754@mail.ru
MD, Associate Professor, Department of Infectious Diseases (with Course of Medical Parasitology and Tropical Diseases) Saint Petersburg, Russia

Vladimir A. Kapatsyna

S.P Botkin Clinical Infectious Diseases Hospital

Email: ingashi@mail.ru
Head, Department Saint Petersburg, Russia

Aleksandr I. Rakin

S.M. Kirov Military Medical Academy Ministry of Defense of the Russian Federation

Email: rakinalex@gmail.com
Educator, Department of Biology (with Course of Medical Genetics) Saint Petersburg, Russia

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