Description du projet
Des antibiotiques ciblant les lipides comme candidats potentiels pour combattre la résistance aux antimicrobiens
La résistance bactérienne aux antibiotiques représente une menace majeure pour la santé mondiale et souligne le besoin urgent de nouveaux antibiotiques dotés de modes de liaison innovants. Les antibiotiques ciblant les lipides (antibiotiques CL) ciblent les lipides présents uniquement dans les membranes cellulaires bactériennes, tuant les pathogènes réfractaires sans résistance détectable. Cependant, le mécanisme moléculaire de l’action des antibiotiques CL demeure peu exploré en raison des difficultés techniques que pose la visualisation des modes de liaison natifs. Le projet champANTIBIOTICS, financé par l’UE, entend éclaircir les modes de liaison natifs des antibiotiques CL dans des bactéries intactes. À cette fin, l’étude fera appel à des méthodes de résonance magnétique nucléaire à l’état solide, des stratégies de marquage isotopique et la microscopie à super-résolution afin de découvrir les mécanismes moléculaires de l’action antibiotique CL de la daptomycine et de nouveaux médicaments provenant de bactéries non cultivables.
Objectif
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
Champ scientifique
- 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
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitution d’accueil
3584 CS Utrecht
Pays-Bas