| Titre : |
Implications of redox mechanisms in the mode of action of antimalarials and resistance to artemisinin |
| Type de document : |
texte imprimé |
| Auteurs : |
Chinedu Egwu, Auteur ; Benoit-Vical, Françoise, Directeur de thèse ; Karine Reybier, Directeur de thèse |
| Année de publication : |
2021 |
| Langues : |
Anglais (eng) |
| Tags : |
MALARIA STRESS OXYDATIF ROS LC- MS ANTIMALARIAL |
| Résumé : |
"Malaria is a vector-borne disease caused by Plasmodium and transmitted by female Anopheles mosquitoes. Despite numerous efforts, malaria remains a major public health problem with more than 400,000 deaths each year. The development of antimalarial drugs is faced with the almost systematic emergence of resistant parasites. Resistance to the current gold standard drug, artemisinin, was first reported in Cambodia in 2008 and has since spread throughout Asia. First cases of resistance have also been reported recently in South America and Africa. There is therefore an urgent need to propose new relevant therapeutic strategies. Our work focused on the study, in Plasmodium falciparum, of the implications of redox mechanisms i) in the mode of action of different antimalarials and ii) in the resistance phenomenon associated with artemisinin. For this, we first developed a new analytical method based on liquid chromatography coupled to mass spectrometry (LC-MS), adapted to the quantification of reactive oxygen species (ROS) in erythrocytes. This protocol thus made it possible to demonstrate the involvement of superoxide radical anions in the mechanism of action of different classes of antimalarial drugs such as artemisinins and atovaquone. In the second segment, we studied the role of redox processes in artemisinin resistance in Plasmodium falciparum, by comparing an artemisinin-sensitive and an artemisinin-resistant strain at the steady state and after artemisinin treatment. Different markers of redox regulation such as ROS production, protein oxidation level and expression of antioxidant molecules or enzyme were compared. We demonstrated, using different original analytical methods, that artemisinin-resistant parasites managed ROS production from artemisinin treatment better than sensitive parasites and that this phenomenon was notably linked to an overexpression of antioxidants. This work brings new perspectives concerning the mechanism of action of major antimalarial drugs and highlights the essential role of redox mechanisms in the resistance of Plasmodium falciparum to artemisinin. These results will be taken into account in the development of new antimalarial drugs in order to bypass artemisinin resistance and win the war against malaria." |
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Université Toulouse 3 |
| Date_soutenance : |
23/03/2021 |
| Ecole_doctorale : |
BSB - Biologie Santé Biotechnologies (Toulouse) |
| Domaine : |
Pharmacologie |
| Localisation : |
LCC |
| En ligne : |
http://www.theses.fr/2021TOU30011 |
Implications of redox mechanisms in the mode of action of antimalarials and resistance to artemisinin [texte imprimé] / Chinedu Egwu, Auteur ; Benoit-Vical, Françoise, Directeur de thèse ; Karine Reybier, Directeur de thèse . - 2021. Langues : Anglais ( eng)
| Tags : |
MALARIA STRESS OXYDATIF ROS LC- MS ANTIMALARIAL |
| Résumé : |
"Malaria is a vector-borne disease caused by Plasmodium and transmitted by female Anopheles mosquitoes. Despite numerous efforts, malaria remains a major public health problem with more than 400,000 deaths each year. The development of antimalarial drugs is faced with the almost systematic emergence of resistant parasites. Resistance to the current gold standard drug, artemisinin, was first reported in Cambodia in 2008 and has since spread throughout Asia. First cases of resistance have also been reported recently in South America and Africa. There is therefore an urgent need to propose new relevant therapeutic strategies. Our work focused on the study, in Plasmodium falciparum, of the implications of redox mechanisms i) in the mode of action of different antimalarials and ii) in the resistance phenomenon associated with artemisinin. For this, we first developed a new analytical method based on liquid chromatography coupled to mass spectrometry (LC-MS), adapted to the quantification of reactive oxygen species (ROS) in erythrocytes. This protocol thus made it possible to demonstrate the involvement of superoxide radical anions in the mechanism of action of different classes of antimalarial drugs such as artemisinins and atovaquone. In the second segment, we studied the role of redox processes in artemisinin resistance in Plasmodium falciparum, by comparing an artemisinin-sensitive and an artemisinin-resistant strain at the steady state and after artemisinin treatment. Different markers of redox regulation such as ROS production, protein oxidation level and expression of antioxidant molecules or enzyme were compared. We demonstrated, using different original analytical methods, that artemisinin-resistant parasites managed ROS production from artemisinin treatment better than sensitive parasites and that this phenomenon was notably linked to an overexpression of antioxidants. This work brings new perspectives concerning the mechanism of action of major antimalarial drugs and highlights the essential role of redox mechanisms in the resistance of Plasmodium falciparum to artemisinin. These results will be taken into account in the development of new antimalarial drugs in order to bypass artemisinin resistance and win the war against malaria." |
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Université Toulouse 3 |
| Date_soutenance : |
23/03/2021 |
| Ecole_doctorale : |
BSB - Biologie Santé Biotechnologies (Toulouse) |
| Domaine : |
Pharmacologie |
| Localisation : |
LCC |
| En ligne : |
http://www.theses.fr/2021TOU30011 |
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Implications of redox mechanisms in the mode of action of antimalarials and resistance to artemisinin
