NABARSI

Executive Summary (and invitation to prospective collaborators)

The NABARSI project has identified inhibitors of aminoacyl-tRNA synthetases (aaRS), enzymes necessary for the production of proteins within bacterial cells (the production of proteins being necessary for survival of bacterial cells). The NABARSI consortium has succeeded in obtaining three new and potentially interesting aaRS antibiotics.  We have been able to establish that they are working through the intended mechanism of action and that they have a spectrum of activity against Gram-negative bacteria, including clinical isolates. 
 
The newly identified compounds are structurally novel and two patent applications have been filed, with further applications expected to be made in the future.
 
Further funding and collaborations are now being sought to fully characterise and exploit the potential of our findings
 
For further information please contact j.hays@erasmusmc.nl (coordinator on behalf of the NABARSI consortium).
 
 
Background
 
NABARSI is an FP7-funded consortium that will develop a cutting-edge drug discovery project to increase the antibacterial pipeline. 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. The NABARSI consortium consists of 5 partners: 2 SMEs - Omnia Molecular S.L. (Spain) and InhibOx (UK), and 3 scientific institutions - Latvian Institute of Organic Synthesis (Latvia); the University of Leeds (UK) and the Erasmus University Medical Centre (ErasmusMC, The Netherlands - Coordinator).    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 ErasmusMC will be assessed. Resistance appearance frequency and mechanisms will also be assessed early by selection and characterization of resistant mutants by ErasmusMC and Leeds. A co-development agreement with pharmaceutical companies will be intensively sought with the aim of exploiting the NCEs upon finalisation of NABARSI.

  • Project duration: 36 months
  • Starting date: June 2013
  • Total budget: €5,389,151.80

                     THE NABARSI TEAM:

  • OMNIA MOLECULAR S.L. (Barcelona) 

  • ERASMUS MC (Rotterdam) (Coordinator)

  • INHIBOX LIMITED (Oxford)

  • LATVIAN INSTITUTE OF ORGANIC SYNTHESIS (Riga)

  • UNIVERSITY OF LEEDS (Leeds)
Funded by a grant from the European Union Framework 7 (FP7) programme - Health.2013.2.31-1 - Grant agreement no: 601725.