Project description DEENESFRITPL A new class of antibiotics may emerge from a long-known class of natural compounds As multidrug resistance to antibiotics increases, the search for new drug candidates becomes more pressing. Carboxyl polyether ionophores (CPIs), also called polyether antibiotics, are a unique class of naturally occurring ionophores. While ionophores (ion transporters) have been highly esteemed and widely used in synthetic chemistry due to their intricate molecular structures, they have been largely eliminated from the study of cellular systems due to unflattering labels like ‘non-specific’ and ‘toxic’. However, CPIs have been shown to have antibacterial, antifungal, antiparasitic and antiviral activity, and tumour cell cytotoxicity in various studies; these characteristics have yet to be exploited. The EU-funded project RECYPION is changing the game, evaluating what is responsible for the antibiotic activity of CPIs, exploring what other activities they may have, and devising a way to synthesise them to harness their innate potential for good. Show the project objective Hide the project objective Objective 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. Fields of science natural sciencesphysical sciencesopticsspectroscopy Keywords RECYPION Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-COG - ERC Consolidator Grant Call for proposal ERC-2019-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution AARHUS UNIVERSITET Net EU contribution € 1 998 864,00 Address NORDRE RINGGADE 1 8000 Aarhus C Denmark See on map Region Danmark Midtjylland Østjylland Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 998 864,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all AARHUS UNIVERSITET Denmark Net EU contribution € 1 998 864,00 Address NORDRE RINGGADE 1 8000 Aarhus C See on map Region Danmark Midtjylland Østjylland Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 998 864,00
