New AntiBacterials with Inhibitory Activity on Aminoacyl-tRNA Synthetases

Nabarsi

http://www.nabarsi.eu/

Acronym:  NABARSI
Funding scheme: CP-FP – Small or medium-scale focused research project
Contract number: 601725
Implementation period:  01.06.2013. – 31.05.2016
Project coordinator: Erasmus University Medical Centre, Netherlands
Project partners:

Omnia Molecular S.L. , Spain
InhibOx, United Kingdom
Latvian Institute of Organic Synthesis, Latvia
University of  Leeds, United Kingdom

Leader of Latvian team: Dr. chem. Aigars Jirgensons
Total costs:          5 389 151,80  EUR
EU contribution:  4 102 157,50  EUR
Costs for Latvian partner: 848 025,00  EUR

Summary
The main goal of NABARSI is to find new chemical entities (NCEs) with antibacterial efficacy in an animal model of multi-drug resistant (MDR) bacterial infection and to exploit the results through obtaining a co-development with industry. Antibacterial activity will be achieved through inhibition of essential aminoacyl-tRNA synthetases (aaRS). Individual aaRS are highly conserved across bacteria, enabling the discovery of broad-spectrum antibacterials. To reduce the likelihood of resistance, NABARSI will look for NCEs with inhibitory activity against multiple aaRS enzymes. InhibOx and LIOS will design NCEs by rational and fragment based drug discovery methods followed by synthetic structure optimization. To increase chemical diversity, virtual screening of large (>100 M) compound libraries available at InhibOx will be performed. Limitations of previous aaRS inhibitors will be overcome by novel approaches such as the in Omnia assay: activity of the compounds on pathogenic aaRS enzyme is measured inside a human cell, allowing rejection of compounds acting through human aaRS and identifying compounds that cross biological membranes. The expertise of Leeds in mode of action studies will be used at an early stage. Activity of the NCEs on clinical isolates of MDR strains available at Erasmus MC will be assessed. Resistance appearance frequency and mechanisms will also be assessed early by selection and characterization of resistant mutants by Erasmus MC and Leeds. A co-development agreement with pharmaceutical companies will be intensively sought with the aim of exploiting the NCEs upon finalisation of NABARSI.