Descripción del proyecto
El entorno espacial y el desarrollo de farmacorresistencia en las bacterias
La administración estándar de antibióticos genera un perfil de concentración no homogéneo, ya que la penetración de medicamentos no es perfecta. Sin embargo, los experimentos «in vitro» llevados a cabo para estudiar la resistencia a los antibióticos suelen tener lugar en entornos líquidos homogéneos. Algunos estudios recientes parecen sugerir que los gradientes espaciales en la concentración de fármacos aceleran el desarrollo de la resistencia, ya que las mutaciones resistentes evolucionan al invadir las zonas ricas en medicamentos. El proyecto EvoSpa, financiado con fondos europeos, se ha propuesto desarrollar un nuevo ensayo experimental en el que las bacterias migran y evolucionan en cientos de entornos creados de forma independiente. El ensayo se basará en la robótica y la manipulación personalizada de líquidos y tendrá el objetivo de crear diferentes escenarios para antibióticos y medir la evolución en distintos entornos. Se espera que la iniciativa sirva para aportar un estudio sistemático y cuantitativo del impacto de la estructura espacial en la dinámica evolutiva.
Objetivo
Given the looming antibiotic resistance crisis, it is imperative to understand the fundamental determinants of resistance evolution dynamics. When antibiotics are administered to a patient, imperfect drug penetration leads to a highly inhomogeneous concentration profile. In contrast, evolution experiments to study resistance are commonly performed in homogeneous liquid environments. Recently, there has been a surge of theoretical studies suggesting that spatial drug concentration gradients drastically accelerate resistance evolution as resistant mutants evade resource competition by invading drug-enriched territory. However, the effect of spatial structure on evolutionary dynamics remains unclear due to a lack of experimental assays with well-defined, inhomogeneous landscapes.
Here, I propose to develop a novel experimental assay where bacteria migrate and evolve on a landscape consisting of hundreds of independently definable environments. This assay will be implemented using custom liquid handling and imaging robots to systematically program antibiotic landscapes and measure evolution on a wide range of drug environments. By combining this novel assay with theoretical modeling, I will investigate evolution in monotonous and rugged drug landscapes. Motivated by theoretical predictions that multi-drug strategies aimed at preventing resistance evolution become compromised in inhomogeneous environments, I will further investigate the effect of spatial inhomogeneity using defined multi-drug landscapes.
This project will provide a unique, quantitative and systematic experimental investigation on how spatial structure affects evolutionary dynamics. Beyond bacteria evolving antibiotic resistance, the same concepts apply for tumor resistance evolution. Overall, this project will greatly advance our understanding of resistance evolution with broad biomedical implications.
Ámbito científico
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesevolutionary biology
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
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Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
50931 Koln
Alemania