Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination
IntroductionThe global evolution of resistance to Artemisinin-based Combination Therapies (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease.MethodsHere, we have used whole genome sequencing to characterize the genetic variation in the experimentally...
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1353057/full |
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| author | Gustavo Capatti Cassiano Axel Martinelli Melina Mottin Bruno Junior Neves Carolina Horta Andrade Carolina Horta Andrade Pedro Eduardo Ferreira Pedro Cravo |
| author_facet | Gustavo Capatti Cassiano Axel Martinelli Melina Mottin Bruno Junior Neves Carolina Horta Andrade Carolina Horta Andrade Pedro Eduardo Ferreira Pedro Cravo |
| author_sort | Gustavo Capatti Cassiano |
| collection | DOAJ |
| description | IntroductionThe global evolution of resistance to Artemisinin-based Combination Therapies (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease.MethodsHere, we have used whole genome sequencing to characterize the genetic variation in the experimentally evolved Plasmodium chabaudi parasite clone AS-ATNMF1, which is resistant to artesunate + mefloquine.Results and discussionFive novel single nucleotide polymorphisms (SNPs) were identified, one of which was a previously undescribed E738K mutation in a 26S proteasome subunit that was selected for under artesunate pressure (in AS-ATN) and retained in AS-ATNMF1. The wild type and mutated three-dimensional (3D) structure models and molecular dynamics simulations of the P. falciparum 26S proteasome subunit Rpn2 suggested that the E738K mutation could change the toroidal proteasome/cyclosome domain organization and change the recognition of ubiquitinated proteins. The mutation in the 26S proteasome subunit may therefore contribute to altering oxidation-dependent ubiquitination of the MDR-1 and/or K13 proteins and/or other targets, resulting in changes in protein turnover. In light of the alarming increase in resistance to artemisin derivatives and ACT partner drugs in natural parasite populations, our results shed new light on the biology of resistance and provide information on novel molecular markers of resistance that may be tested (and potentially validated) in the field. |
| first_indexed | 2024-03-07T19:10:45Z |
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| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-03-07T19:10:45Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-ce4b8e5c6f0f4e7d8e8946cbdb66c3932024-03-01T04:42:18ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882024-03-011410.3389/fcimb.2024.13530571353057Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combinationGustavo Capatti Cassiano0Axel Martinelli1Melina Mottin2Bruno Junior Neves3Carolina Horta Andrade4Carolina Horta Andrade5Pedro Eduardo Ferreira6Pedro Cravo7Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health, (LA-REAL), Instituto de Higiene e Medicina Tropical, (IHMT), Universidade NOVA de Lisboa, (UNL), Lisbon, PortugalBigOmics Analytics, Lugano, SwitzerlandLaboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, BrazilLaboratory or Cheminformatics (LabChem), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, BrazilLaboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, BrazilCenter for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirão Preto, University of São Paulo, Ribeirão Preto, BrazilLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, PortugalGlobal Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health, (LA-REAL), Instituto de Higiene e Medicina Tropical, (IHMT), Universidade NOVA de Lisboa, (UNL), Lisbon, PortugalIntroductionThe global evolution of resistance to Artemisinin-based Combination Therapies (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease.MethodsHere, we have used whole genome sequencing to characterize the genetic variation in the experimentally evolved Plasmodium chabaudi parasite clone AS-ATNMF1, which is resistant to artesunate + mefloquine.Results and discussionFive novel single nucleotide polymorphisms (SNPs) were identified, one of which was a previously undescribed E738K mutation in a 26S proteasome subunit that was selected for under artesunate pressure (in AS-ATN) and retained in AS-ATNMF1. The wild type and mutated three-dimensional (3D) structure models and molecular dynamics simulations of the P. falciparum 26S proteasome subunit Rpn2 suggested that the E738K mutation could change the toroidal proteasome/cyclosome domain organization and change the recognition of ubiquitinated proteins. The mutation in the 26S proteasome subunit may therefore contribute to altering oxidation-dependent ubiquitination of the MDR-1 and/or K13 proteins and/or other targets, resulting in changes in protein turnover. In light of the alarming increase in resistance to artemisin derivatives and ACT partner drugs in natural parasite populations, our results shed new light on the biology of resistance and provide information on novel molecular markers of resistance that may be tested (and potentially validated) in the field.https://www.frontiersin.org/articles/10.3389/fcimb.2024.1353057/fullplasmodiumdrug resistanceartemisinin combination treatmentgenomicsmolecular dynamics simulations |
| spellingShingle | Gustavo Capatti Cassiano Axel Martinelli Melina Mottin Bruno Junior Neves Carolina Horta Andrade Carolina Horta Andrade Pedro Eduardo Ferreira Pedro Cravo Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination Frontiers in Cellular and Infection Microbiology plasmodium drug resistance artemisinin combination treatment genomics molecular dynamics simulations |
| title | Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination |
| title_full | Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination |
| title_fullStr | Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination |
| title_full_unstemmed | Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination |
| title_short | Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination |
| title_sort | whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate atn and to atn mefloquine combination |
| topic | plasmodium drug resistance artemisinin combination treatment genomics molecular dynamics simulations |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1353057/full |
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