Periodic Reporting for period 1 - NEXTER (Next generation eco-friendly, microbiome preserving and reduced resistance therapeutics)
Okres sprawozdawczy: 2019-07-01 do 2020-12-31
This PoC program was based on our breakthroughs that were accomplished by our ERC-funded project (entitled as "Novel Insights into Multi-drug Resistance to Antibiotics and the Primordial Ribosome-NOVRIB”, Grant Agreement no. 322581).
In this PoC project, we extended our studies to additional pathogens and advanced the identification of novel next generation eco-friendly, novel compounds, including cellular penetration. We expect that our studies will lead to the commercialization of the compounds that associate with the newly discovered novel target sites for the design of novel synthetic antibiotics. Since methods for clinical swift identification of pathogens, have been recently developed, our studies, once fully matured, should open the way for efficient usage of our designed species-specific antibiotics.
In particular, we determined the structures of ribosomal particles from several pathogenic life-threatening bacteria and eukaryots, such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium, Leishmania donovani as well as Euglena gracilis, a phylogenetic related organism of the pathogenic protozoa Trypanosomes and Leishmania, which are major players in the field of multi-drug resistance. These structures provided us with unique chemical tools for (a) understanding structural variations caused by the AMR acquiring process and (b) identifying novel exposed structural motifs, mainly rRNA segments located on the ribosome’s surface. Among these, we have identified some of those that can be exploited as potential targets for novel antibiotics, for which no resistance genes against them are currently existing, since they are located away from the main targets of current clinically used drugs, namely the ribosomal active regions.
In short: we determined and exploited the 3D high-resolution structures of the ribosome from bacterial and parasite pathogens for specific targeting. Following target identification, we were able to inhibit the activity of ribosomes from various pathogens using our designed compounds, based on targeting these novel sites.
The chemical properties of these targeting compounds are currently adapted and will be further optimized to be environmentally friendly therefore leading to reduced resistance and for the conservation of the human microbiome.
In this PoC project, we extended our studies to additional pathogens and advanced the identification of novel next generation eco-friendly, novel compounds, including cellular penetration. We expect that our studies will lead to the commercialization of the compounds that associate with the newly discovered novel target sites for the design of novel synthetic antibiotics. Since methods for clinical swift identification of pathogens, have been recently developed, our studies, once fully matured, should open the way for efficient usage of our designed species-specific antibiotics.
In particular, we determined the structures of ribosomal particles from several pathogenic life-threatening bacteria and eukaryots, such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium, Leishmania donovani as well as Euglena gracilis, a phylogenetic related organism of the pathogenic protozoa Trypanosomes and Leishmania, which are major players in the field of multi-drug resistance. These structures provided us with unique chemical tools for (a) understanding structural variations caused by the AMR acquiring process and (b) identifying novel exposed structural motifs, mainly rRNA segments located on the ribosome’s surface. Among these, we have identified some of those that can be exploited as potential targets for novel antibiotics, for which no resistance genes against them are currently existing, since they are located away from the main targets of current clinically used drugs, namely the ribosomal active regions.
In short: we determined and exploited the 3D high-resolution structures of the ribosome from bacterial and parasite pathogens for specific targeting. Following target identification, we were able to inhibit the activity of ribosomes from various pathogens using our designed compounds, based on targeting these novel sites.
The chemical properties of these targeting compounds are currently adapted and will be further optimized to be environmentally friendly therefore leading to reduced resistance and for the conservation of the human microbiome.