Descrizione del progetto
Antibiotici che colpiscono i lipidi come nuovi candidati per combattere la resistenza antimicrobica
La resistenza batterica agli antibiotici rappresenta una grave minaccia per la salute a livello globale e mette in evidenza l’urgente necessità di nuovi antibiotici dotati di modalità di legame inedite. Gli antibiotici che colpiscono i lipidi (LT, lipid-targeting), destinati a lipidi che si trovano esclusivamente nelle membrane cellulari batteriche, uccidono gli agenti patogeni refrattari senza che sia possibile rilevare alcuna resistenza. Ciononostante, il meccanismo molecolare alla base dell’azione ad opera degli antibiotici LT non è tuttora stato approfondito a causa delle sfide tecniche insite nella visualizzazione delle modalità di legame native. Il progetto champANTIBIOTICS, finanziato dall’UE, intende chiarire le modalità di legame native degli antibiotici LT in batteri intatti. A tal fine, lo studio impiegherà vari strumenti, quali metodi di risonanza magnetica nucleare, strategie di etichettatura isotopica e microscopia a super risoluzione, per svelare i meccanismi molecolari alla base dell’azione antibiotica LT della daptomicina e di nuovi farmaci a partire da batteri non coltivabili.
Obiettivo
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
Campo scientifico
- 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
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
3584 CS Utrecht
Paesi Bassi