Design and Chemical Construction of Quasi-living Phagocytic Synthetic Cells for Artificial Phagocytosis of Bacteria

Descripción del proyecto

Células sintéticas fagocíticas contra cepas resistentes a antibióticos

El aumento de las infecciones resistentes a antimicrobianos, sumado a la falta de avances en el desarrollo de antibióticos, supone una amenaza para la salud mundial. En el proyecto PhagoSynCell, financiado por el Consejo Europeo de Investigación, se desarrollarán células sintéticas fagocíticas capaces de reconocer, capturar, engullir y eliminar selectivamente bacterias resistentes a antibióticos sin favorecer su resistencia. En primer lugar, el equipo del proyecto diseñará membranas para esas células utilizando nuevos anfifilos macromoleculares ensamblados en vesículas funcionalmente diversas. Se explorarán métodos para mejorar la captación de microobjetos mediante actuadores mecánicos a nivel molecular, incorporando una superselectividad en membranas artificiales para un direccionamiento preciso hacia bacterias. Para validar su planteamiento, se evaluará la eficacia y bioseguridad de las células sintéticas fagocíticas frente a cepas resistentes a antibióticos en células, organoides y modelos tisulares. En PhagoSynCell se pretende sentar las bases de la fagocitosis artificial para crear células sintéticas capaces de eliminar bacterias de forma selectiva, lo cual podría suponer un gran avance en la lucha contra la resistencia a los antimicrobianos.

Objetivo

The growing occurrence of antimicrobial-resistant infections, compounded with the stalling development and approval of new antibiotic drugs, has created a therapeutic gap, threatening a global health crisis. Resistance emerges when bacteria mutate their molecular targets for antibiotics, evading their action. Is it conceivable to design synthetic cells assembled from abiotic synthetic macromolecules, capable of mimicking the most salient features of phagocytosis —Nature’s most selective, effective, and advanced strategy to eradicate pathogens? The aim of PhagoSynCell is to create Phagocytic Synthetic Cells (PSCs) that selectively recognize, capture, engulf and kill antibiotic-resistant bacteria without generating selection pressure for resistance. Firstly, we will develop the membrane of the PSCs by the simulation-aided synthesis of novel macromolecular amphiphiles (Janus dendrimers and amphiphilic comb polymers) self-assembled into vesicle libraries with functional diversity and phenotype programmability. We will then study novel methods to facilitate engulfment of micro-objects by leveraging principles of mechanical actuation programmed at the molecular level. We will introduce superselectivity to artificial membranes to selectively capture bacteria. Furthermore, we will develop an antimicrobial strategy triggered and activated by engulfment that disrupts the bacterial membrane —an element highly unsusceptible to evolution. Finally, we will demonstrate the efficacy of PSCs against pathogenic antibiotic-resistant strains and show their biosafety in cells, organoids, and advanced tissue models as proof-of-concept for future applications. PhagoSynCell will unveil the underlying principles of Artificial Phagocytosis, delivering synthetic cells able to selectively recognize and kill bacteria. Ultimately, this will provide the steppingstone towards the use of synthetic cells as a quasi-living therapeutic —a field I envision will revolutionize medicine.