Project: TRIC inhibitors to switch-off antimicrobial resistance

„The world is on the brink of losing antibiotics as miracle drugs“ stated Dr. Margret Chan, WHO Director. Despite the recognized urgent need for new antimicrobials for clinical use (reflected by the recent and ongoing IMI and FP7 initiatives focusing on antimicrobial resistance), in particular for the treatment of multi-resistant clinical pathogens, many drug developers have left the field. Furthermore, the critical challenge of rapidly expanding antimicrobial resistance is far from being adequately addressed today, as evidenced by the low number of new products in clinical development and the lack of novel first-in-class therapeutics interacting with previously untargeted bacterial proteins. The SARTRIC project addresses this deficiency by restoring vancomycin activity and thus restoring the efficacy of an already marketed antibiotic. The two Ps BioVersys AG (Basel, Switzerland) and SARomics Biostructures AB (Lund, Sweden) combine their highly complementary technology modules, expertise and resources to drive the drug development process of initial Hit molecules towards fully characterized Leads that qualify for preclinical testing. BioVersys TRIC (Transcription Regulator Inhibitory Compound) technology platform allows for the identification and characterization of novel target-specific, non-toxic and non-antibacterial small molecules that restore the activity of antibiotics by blocking the transcriptional activation of resistance genes. The combinatorial application of BioVersys TRIC adjuvant compounds with existing antibiotics has been shown to allow for killing of extensively resistant pathogens at clinically relevant doses of the antibiotic in vitro and in vivo. BioVersys has identified a series of small chemical compounds that specifically interfere with VanR-mediated transcriptional activation of vancomycin resistance genes and thus restore the activity of vancomycin. This potentially game-changing approach is highly targeted towards VanR protein isoforms and thus (additionally to the data generated by TRIC assay modules) requires a detailed understanding of VanR 3D structure to guide efficient compound optimization processes. Hence, SARomics Biostructures will contribute their structural biology expertise to SARTRIC. Within the proposed project they will pursue a strategy based on the combination of 3D structural information from the target proteins, fragment-based drug design (FBDD) and computer-aided drug design for the improvement of existing TRIC compounds and for the development of fragments to mature compounds with novel chemotypes. The use of these state-of-the-art technologies will result in a substantial acceleration of the proposed drug discovery process. The project will also prove the ability of the new SME Pship to generate new lead molecules efficiently, considerably raising their competitiveness on the market and contributing to the creation of a new anti-infective lead generation platform. SARTRIC will result in i) nomination of a preclinical candidate that qualifies for EMA CTA enabling studies ii) identification of further Lead backbone structures out of the fragment based drug discovery and iii) development of a HTS crystallography based drug discovery platform that enables routine screening of the target protein family of transcriptional regulators. The ambitious goals and timelines (24 months total) will be achieved by combining the highly integrated and rapid technology platforms of the parties and cost-efficient outsourcing of standardized development routines to experienced and specialized Ps. Due to the individual business models of BioVersys (R&D) and SARomics Biostructures (technology driven fee-for-service platform) and the deliverables of SARTRIC, the distribution of 70/30 of total project funding reflects well the major cost drivers of the drug development modules and justifies the leading role of BioVersys in exploiting the results of SARTRIC towards clinical phases after SARTRIC finalization .

Acronym	SARTRIC (Reference Number: 8139)
Duration	01/10/2013 - 30/09/2015
Project Topic	Antimicrobial resistance is a major global public health threat and societal burden with a high unmet medical need. SARTRIC addresses this growing problem with the development of small-molecule inhibitors that switch-off resistance gene expression and thus restore antibiotic activity.
Network	Eurostars
Call	Eurostars Cut-Off 10

Project partner

Number	Name	Role	Country
2	BioVersys AG	Coordinator	Switzerland
2	SARomics Biostructures AB	Partner	Sweden