Informations générales
Intitulé de l'offre : M/F Thesis on modeling the impact of mutations on the structure and activity of Plasmodium falciparum dihydropterate synthase (H/F)
Référence : UPR8001-MARBRU-004
Nombre de Postes : 1
Lieu de travail : TOULOUSE
Date de publication : mercredi 16 avril 2025
Type de contrat : CDD Doctorant
Durée du contrat : 36 mois
Date de début de la thèse : 1 septembre 2025
Quotité de travail : Complet
Rémunération : 2200 gross monthly
Section(s) CN : 20 - Biologie moléculaire et structurale, biochimie
Description du sujet de thèse
Gestational malaria remains a major public health problem, responsible for significant morbidity and mortality in both pregnant women and fetuses. In addition to vector protection measures, the sulfadoxine-pyrimethamine (SP) combination is used throughout sub-Saharan Africa for intermittent preventive treatment (IPT) in pregnant women. SP blocks the folate biosynthesis pathway, by inhibiting two enzymes: dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), respectively. However,
its efficacy is threatened by the appearance of mutations in the genes coding for DHFR and DHPS in Plasmodium falciparum. A new PfDHPS mutation, I431V, was identified in Nigeria in 2007, then in Cameroon in 2010. This mutation was mainly found in association with 4 other PfDHPS mutations (S436A, A437G, A581G and A613S), forming a quintuple vagKgs mutant. Analogy with some highly mutated genotypes suggests that this PfDHPS quintuple mutant may have a high level of sulfadoxine resistance. To date, few data are available concerning this I431V mutation.
The aim of the project of which this thesis is a part is to understand the role and impact of this new I431V mutation of PfDHPS, and the associated mutants. To answer this question, joint studies are being carried out on epidemiology, phenotype and enzyme/substrate molecular interactions. The latter is where our simulation activities come into play. They are threefold: i) exploration of enzyme structure and dynamics (classical DM); ii) study of enzyme activity (QMM DM); iii) docking of new molecules, taking into account the impact of the mutations explored. This thesis will cover in particular the last 2 aspects.
Contexte de travail
The candidate will have a solid background in physics or computational chemistry and QMM techniques adapted to biomolecules. Knowledge of in silico screening is a plus.
Le poste se situe dans un secteur relevant de la protection du potentiel scientifique et technique (PPST), et nécessite donc, conformément à la réglementation, que votre arrivée soit autorisée par l'autorité compétente du MESR.
Contraintes et risques
None.