

Analysis of drug resistance in Plasmodium falciparum – the causative agent of imported tropical malaria in St. Petersburg (molecular-genetic research)
https://doi.org/10.33667/2078-5631-2024-4-42-45
Abstract
Drug resistance to Plasmodium falciparum is a leading cause of ineffective etiotropic therapy for tropical malaria in non-immune individuals returning from regions endemic for this infection. Genetic markers of resistance to major antimalarial drugs are single nucleotide polymorphisms of genes such as PfCRT, PfMDR 1, PfDHFR, PfDHPS, PfATP6, and PfKelch 13, which encode key proteins involved in the metabolism parasites cells. PCR-based methods using alternative primer technology and real-time PCR were used to examine venous blood samples from 63 tropical malaria patients treated in infectious diseases hospitals in St. Petersburg during 2018–2023. The study found that the most frequently detected genetic markers of P. falciparum drug resistance in patients blood samples with imported tropical malaria were S 1034C (58.7 %), A578S (55.56 %) and S 108N (49.21 %). The D 1246Y (4.76 %) and A630S (6.35 %) mutations were less frequent. The majority of cases showed mutations in the PfMDR 1 gene (over 76 %). Polymorphisms in the PfATP6 and PfCRT genes were detected in 32 % and 14 % of cases, respectively. In most cases, markers of parasite resistance to mefloquine and its derivatives were present (about 80 %). The proportion of P. falciparum resistance markers to artemisinin and its derivatives was about 63.5 %, and to sulfadoxine-pyrimethamine, less than 10 %. The study found that 39 % of cases showed genetic markers of resistance to both mefloquine and artemisinin, while 35 % of cases showed resistance to both mefloquine and sulfadoxine. Therefore, it is recommended to prescribe combination drugs with different mechanisms of pharmacological action for the treatment in each specific case of tropical malaria. Combining this approach with laboratory methods for early determination of the malaria drug resistance will reduce the latal cases.
About the Authors
A. R. AryukovRussian Federation
Aryukov Artem R., teacher of the Department of Biology
ResearcherId: IAO-0519–2023
St. Petersburg
V. A. Kapatsyna
Russian Federation
Kapatsyna Vladimir A., head of Dept, infectious disease physician
St. Petersburg
A. I. Soloviev
Russian Federation
Soloviev Alexey I., DM Sci (habil.), associate professor, head of Dept of Biology
St. Petersburg
A. N. Kovalenko
Russian Federation
Kovalenko Alexander N., DM Sci (habil.), associate professor of Dept of Infectious Diseases with a course in Medical Parasitology and Tropical Diseases
St. Petersburg
V. A. Romanenko
Russian Federation
Romanenko Vladimir A., preparator at Dept of Biology
St. Petersburg
R. V. Gudkov
Russian Federation
Gudkov Roman V., PhD Med, senior lecturer at Dept of Infectious Diseases with a course in Medical Parasitology and Tropical Diseases
St. Petersburg
A. S. Zinin
Russian Federation
Zinin Artem S., scientific company operator
St. Petersburg
References
1. Sergiev V. P., Baranova A. M., Kozhevnikova G. M., Tokmalayev A. K., Chernyshov D. V., Chentsov V. B., Kouassi D. M. Problems of clinical diagnosis and treatment of P. falciparum malaria in Russian Federation. Therapeutic Archive.2018; 90(11): 4–8. (In Russ.) https://doi.org/10.26442/terarkh201890114–8
2. Yasri S., Wiwanitkit V. Artemisinin resistance: An important emerging clinical problem in tropical medicine. International Journal of Physiology, Pathophysiology and Pharmacology. 2021;(6):152.
3. Maiga H. et al. Selection of pfcrt K76 and pfmdr1 N 86 coding alleles after uncomplicated malaria treatment by artemether-lumefantrine in Mali. International journal of molecular sciences. 2021;(11):6057 https://doi.org/10.3390%2Fijms22116057
4. Huang F. et al. Molecular surveillance of pfcrt, pfmdr1 and pfk13-propeller mutations in Plasmodium falciparum isolates imported from Africa to China. Malaria journal. 2021;(20): 1–11. https://doi.org/10.1186/s12936–021–03613–5
5. Calçada C. Expansion of a specific Plasmodium falciparum PfMDR 1 haplotype in Southeast Asia with increased substrate transport. MBio. 2020;(6) https://doi.org/10.1128/mbio.02093–20
6. Nguetse C. N., Adegnika A. A., Agbenyega T., Ogutu B. R., Krishna S., Kremsner P. G., Velavan T. P. Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria. Malaria Journal. 2017;(16): 1–9. https://doi.org/10.1186%2Fs12936–017–1868-y
7. Chenet S. M., Okoth S. A., Kelley J., Lucchi N., Huber C. S., Vreden S., Adhin M. R. Molecular profile of malaria drug resistance markers of Plasmodium falciparum in Suriname. Antimicrobial agents and chemotherapy.2017; 61(7): 10–1128.https://doi.org/10.1128%2FAAC.02655–16
8. Verity R., Aydemir O., Brazeau N. F., Watson O. J., Hathaway N. J., Mwandagalirwa M. K., Juliano J. J. The impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC. Nature communications.2020; 11(1): 2107.https://doi.org/10.1038/s41467–020–15779–8
9. Krishna S. Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends in parasitology. 2010;(11): 517–523.https://doi.org/10.1016/j.pt.2010.06.014
10. Brasil L. W. Pfatp6 molecular profile of Plasmodium falciparum isolates in the western Brazilian Amazon. Malaria Journal. 2012;(11):1–5. https://doi.org/10.1186/1475–2875–11–111
11. Wicht K. J., Mok S., Fidock D. A. Molecular mechanisms of drug resistance in Plasmodium falciparum malaria. Annual review of microbiology. 2020;(74): 431–454.https://doi.org/10.1146%2Fan-nurev-micro-020518–115546
12. Yan H. High frequency mutations in pfdhfr and pfdhps of Plasmodium falciparum in response to sulfadoxine-pyrimethamine: a cross-sectional survey in returning Chinese migrants from Africa. Frontiers in Cellular and Infection Microbiology. 2021;587. https://doi.org/10.3389/fcimb.2021.673194
13. Jiang T. High prevalence of Pfdhfr–Pfdhps quadruple mutations associated with sulfadoxine–pyrimethamine resistance in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea. Malaria journal. 2019;(18):1–8. https://doi.org/10.1186/s12936–019–2734-x
14. Artem Ariukov, Alexey Solovev, Anna Krutikova, Alexander Kovalenko, Vladimir Kapatsyna, Vladimir Romanenko. Development of a technique for analyzing the lengths of restriction fragments to assess the mefloquine resistance of plasmodium falciparum based on the identification of single-nucleotide polymorphisms (A958146T, A961013G, G961625T) of the PFMDR 1 gene. Bulletin of the Russian Military Medical Academy 25.2.2023; 249–260. WEB. https://doi.org/10.17816/brmma387427
15. Kovalenko A. N., Karev V. E., Solovyev A. I., Vasilyeva M. V., Isakov A. N., Kapatsyna V. A. Tropical malaria with a fatal outcome. Arkhiv Patologii. 2020;82(6):50–54. (In Russ.). https://doi.org/10.17116/patol20208206150
16. Sambrook J., Russell D. W. Purification of nucleic acids by extraction with phenol: chloroform. Cold Spring Harbor Protocols. 2006;(1): pdb.prot4455. https://doi.org/10.1101/pdb.prot4455
Review
For citations:
Aryukov A.R., Kapatsyna V.A., Soloviev A.I., Kovalenko A.N., Romanenko V.A., Gudkov R.V., Zinin A.S. Analysis of drug resistance in Plasmodium falciparum – the causative agent of imported tropical malaria in St. Petersburg (molecular-genetic research). Medical alphabet. 2024;(4):42-45. (In Russ.) https://doi.org/10.33667/2078-5631-2024-4-42-45