Projektbeschreibung
Auf Lipide abzielende Antibiotika als neue Kandidaten im Kampf gegen die antimikrobielle Resistenz
Bakterielle Resistenzen gegen Antibiotika stellen eine große Bedrohung für die Weltgesundheit dar und unterstreichen den dringenden Bedarf an neuen Antibiotika mit neuartigen Bindungsmechanismen. Auf Lipide abzielende Antibiotika richten sich gegen Lipide, die nur in bakteriellen Zellmembranen vorkommen, und zerstören refraktäre Krankheitserreger ohne nachweisbare Resistenz. Der molekulare Wirkmechanismus von auf Lipide abzielende Antibiotika ist jedoch noch nicht ausreichend erforscht, da es technisch schwierig ist, die nativen Bindungsmechanismen sichtbar zu machen. Das EU-finanzierte Projekt champANTIBIOTICS zielt darauf ab, die nativen Bindungsmodi von auf Lipide abzielenden Antibiotika in intakten Bakterien zu erforschen. Zu diesem Zweck werden im Rahmen der Studie Methoden der kernmagnetischen Resonanz im Festzustand, Isotopenmarkierungsstrategien und die Super-Resolution-Mikroskopie eingesetzt, um die molekularen Mechanismen der auf Lipide abzielenden Antibiotikawirkung von Daptomycin und neuartigen Wirkstoffen aus nicht kultivierbaren Bakterien aufzudecken.
Ziel
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
Wissenschaftliches Gebiet
- 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
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
3584 CS Utrecht
Niederlande