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Financement de l’UE (2 000 000 €) : Déterminer les mécanismes des antibiotiques ciblant les lipides chez les bactéries intactes Hor01/06/2022 Programme de recherche et d'innovation de l'UE « Horizon »
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Déterminer les mécanismes des antibiotiques ciblant les lipides chez les bactéries intactes
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
| Universiteit Utrecht | 2 000 000 € |
https://cordis.europa.eu/project/id/101045485
Cette annonce se réfère à une date antérieure et ne reflète pas nécessairement l’état actuel. L’état actuel est présenté à la page suivante : Universiteit Utrecht, Utrecht, Pays-Bas.
