Project description
Lipid-targeting antibiotics as a novel candidate to combate antimicrobial resistance
Bacterial resistance to antibiotics represents a major threat to global health and highlights the urgent need for new antibiotics with novel binding modes. Lipid-targeting antibiotics (LT antibiotics) target lipids found only in bacterial cell membranes, killing refractory pathogens without detectable resistance. However, the molecular mechanism of LT antibiotics action remains underinvestigated due to technical challenges in visualising native binding modes. The EU-funded champANTIBIOTICS project aims to elucidate native binding modes of LT antibiotics in intact bacteria. To this end, the study will employ solid-state nuclear magnetic resonance methods, isotope-labelling strategies, and super-resolution microscopy as tools to uncover the molecular mechanisms of LT antibiotic action of daptomycin and of novel drugs from unculturable bacteria.
Objective
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
Fields of science
- 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
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
3584 CS Utrecht
Netherlands