Descripción del proyecto
Antibióticos dirigidos a lípidos como nuevos candidatos para combatir la resistencia a los antimicrobianos
La resistencia bacteriana a los antibióticos representa una amenaza importante para la salud mundial y destaca la necesidad urgente de nuevos antibióticos con nuevos modos de unión. Los antibióticos dirigidos a lípidos (antibióticos LT, por sus siglas en inglés) se dirigen a los lípidos que se encuentran solo en las membranas de las células bacterianas, matando a los patógenos refractarios sin detectar resistencia. Sin embargo, el mecanismo de acción de los antibióticos LT sigue estando poco investigado debido a las dificultades técnicas para visualizar los modos de unión nativos. El proyecto champANTIBIOTICS, financiado con fondos europeos, aspira a dilucidar los modos de unión nativos de los antibióticos LT en bacterias intactas. Para este fin, el estudio utilizará métodos de resonancia magnética nuclear de estado sólido, estrategias de marcado isotópico y microscopia de superresolución como herramientas para desvelar los mecanismos moleculares de la acción antibiótica LT de la daptomicina y de nuevos fármacos a partir de bacterias que no se pueden cultivar.
Objetivo
Antimicrobial resistance is a major threat to global health. To combat this threat, new antibiotics with novel binding modes are urgently needed. Ideal candidates could be lipid-targeting antibiotics (LT-antibiotics) that target special lipids that only exist in bacterial, but not in human cell membranes. These drugs kill refractory pathogens without detectable resistance. This has generated huge interest. So far, the molecular mechanisms of LT-antibiotics have proven elusive due to technical challenges: 1) structures of small drug?lipid complexes in membranes cannot be solved by traditional methods; 2) LT-antibiotics need to oligomerize to become active; and 3) binding modes are strongly affected by cell membrane profiles. In consequence, it has been impossible to visualize native binding modes and an entire class of potent antibiotics remains poorly understood. In pioneering studies on the drug teixobactin, my lab recently presented the first quantitative insights into the mechanisms of LT-antibiotics in cell membranes. Strikingly, we discovered that teixobactin uses a novel ?double attack? type of antimicrobial action, in which teixobactin forms large oligomers that both block the peptidoglycan synthesis and damage bacterial membranes. These findings raise new questions about LT-antibiotics. I propose to establish a comprehensive understanding of LT-antibiotics by elucidating their native binding modes in intact bacteria and at several length-scales (? to ?m). To this end, I will develop solid-state NMR methods, isotope-labelling strategies, and super-resolution microscopy setups. With these tools, I will elucidate the mechanisms of some of the most promising antibiotics of our time: 1) novel drugs from unculturable bacteria; and 2) daptomycin, a front-line drug whose mechanism has been chased by two generations of scientists. This research will outline groundbreaking strategies for determining antibiotic mechanisms and, in so doing, address a pressing
Ámbito científico
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
3584 CS Utrecht
Países Bajos