Descripción del proyecto
La evolución de las enzimas de resistencia a los antibióticos en bacterias
La resistencia a los antibióticos representa uno de los mayores retos de salud pública de nuestra época. La aparición de bacterias resistentes interfiere con la actividad de los antibióticos disponibles y altera sobremanera los procedimientos rutinarios y la hospitalización. La hipótesis de trabajo del proyecto PROBYDE, financiado con fondos europeos, es que la evolución de la resistencia a los antibióticos es consecuencia de cambios genéticos repetibles. Sus investigadores realizarán experimentos de evolución dirigida para comprender los factores determinantes de esta repetibilidad. El trabajo se centrará en las enzimas implicadas en la farmacorresistencia y aportará información fundamental sobre cómo las mutaciones obligan a moléculas clave a seguir trayectorias adaptativas específicas.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesevolutionary biology
- natural sciencesbiological sciencesgeneticsmutation
- agricultural sciencesagriculture, forestry, and fisheriesagriculture
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
28040 Madrid
España