Description du projet
Évolution des enzymes de résistance aux antibiotiques chez les bactéries
La résistance aux antibiotiques représente l’un des plus grands défis en termes de santé publique de notre époque. L’apparition de bactéries résistantes interfère avec l’activité des antibiotiques existants et perturbe de manière aiguë les procédures quotidiennes et les hospitalisations. Le projet PROBYDE, financé par l’UE, repose sur l’hypothèse que l’évolution de la résistance aux antibiotiques est la conséquence de modifications génétiques répétables. Les chercheurs mèneront des expériences d’évolution dirigée afin de comprendre les déterminants de cette répétabilité. Leurs travaux porteront sur les enzymes impliquées dans la résistance aux médicaments et apporteront des informations fondamentales sur la manière dont les mutations contraignent les molécules clés à suivre des voies d’adaptation spécifiques.
Objectif
The fast evolution of bacterial pathogens towards antibiotic resistance is estimated by 2050 to be killing 10 million people every year. Consequently, much interest is being directed towards finding ways to curb or even arrest this evolutionary process. Of note, sequencing efforts are revealing that many of the genetic changes that drive resistance evolution are often repeatable. Understanding what drives this repeatability is of foremost importance if we ever want to develop interventions aimed at anticipating and preventing the evolution of undesirable variants. Here, I will aim at advancing our understanding of evolutionary repeatability in several clinically-relevant, drug-resistance enzymes spanning a range of GC compositions. I will use this relevant model system to empirically test recent predictions on the roles of mutation bias and GC content in shaping mutational pathways. To this end, I will conduct high-throughput 'in vitro' Directed Evolution experiments to explore the potential adaptive paths available via single step mutations among the drug-resistance enzymes. Next, I will compare these 'in vitro' predictions with the outcomes of highly-parallel antibiotic adaptation experiments conducted with bacterial strains with strong mutation biases (e.g. mutators) carrying the same panel of enzymes. By producing important insights into some of the key determinants of evolutionary repeatability, PROBYDE aspires to form a knowledge base that may help harness evolution not only in bacterial pathogens, but also in other human-relevant systems such as cancer, crop pests and industrial microbes.
Champ scientifique
- natural sciencesbiological sciencesevolutionary biology
- natural sciencesbiological sciencesgeneticsmutation
- agricultural sciencesagriculture, forestry, and fisheriesagriculture
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
28040 Madrid
Espagne