Descrizione del progetto
Una nuova classe di antibiotici potrebbe emergere da una classe di composti naturali nota da tempo
Con l’aumento della multifarmacoresistenza agli antibiotici, la ricerca di nuovi farmaci candidati si fa più urgente. Gli ionofori polieteri carbossilici, anche noti come antibiotici polietere, sono una classe unica di ionofori naturali. Sebbene siano stati estremamente stimati e ampiamente utilizzati nella chimica sintetica viste le loro strutture molecolari intricate, gli ionofori (ioni trasportatori) sono stati in gran parte eliminati dallo studio dei sistemi cellulari a causa di etichette poco lusinghiere quali «non specifici» o «tossici». Tuttavia, gli ionofori polieteri carbossilici hanno dimostrato in vari studi di possedere un’attività antibatterica, antifungina, antiparassitaria e antivirale, nonché citotossicità contro le cellule tumorali: tutte caratteristiche che devono ancora essere sfruttate. Il progetto RECYPION, finanziato dall’UE, sta cambiando le regole del gioco, indagando le cause dell’attività antibiotica degli ionofori polieteri carbossilici, esplorando altre possibili attività e ideando un nuovo modo per sintetizzarli, per sfruttarne a fin di bene l’innato potenziale.
Obiettivo
The carboxyl polyether ionophores (CPIs) is a class of >150 complex natural products. Belonging to the most complicated of Nature's secondary metabolites, they are darlings within total chemical synthesis, however, the biological role of these agents is obscure. Due to their canonical function of equilibrating ion-gradients across biological membranes, CPIs are thought to be unspecific and largely uninteresting. Here, I will advocate and demonstrate the opposite position: that not only are these compounds extremely interesting with respect to their complex effects on cells, they also harbor a unique anti-microbial activity that should be a strong priority as we stagger towards a post-antibiotic era. With RECYPION my team and I will draw these compounds back into the spotlight. We will ask the following fundamental questions: 1. Can we develop a synthesis-paradigm that will significantly expand the CPI-chemical space to fully explore their anti-microbial activities? 2. What are the molecular determinants that control the antibiotic-potential of the CPIs, and how do these relate to the mechanism of ion-transport? 3. Can we uncover the cellular activities of CPIs – perhaps even “dark” activities that do not involve ion-transport? We will pioneer a CPI-synthesis-approach based on the ability to recycle complex components from highly abundant CPI-family members. To do so, we will develop novel chemical transformations to deconstruct these molecules which may find broader use in a world that is increasingly focused on how to preserve resources. We will provide the first real experimental characterization of the molecular mechanism by which CPIs mediate ion transport by using ultrafast surface-sensitive spectroscopy on membrane-resident CPIs along with unprecedented structural insight using ultra-high field NMR. Finally, we will use an image-based screening technology called morphological profiling to reveal completely new cellular activities of the CPIs.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
8000 Aarhus C
Danimarca