In order to maximize time resources, the majority of the WPs will initiate as soon as the project commences (except for WP7 regarding Advanced Compound Characterization). Relevant WP activities will be carried out using reference or standard compounds (some aaRS inhibitor compounds are already available as controls) until NCE compounds have been generated, which will allow assay validation to begin as soon as possible and also will provide starting points for the project.
WP1: Management will be provided by Omnia and Erasmus MC.
WP2: Compound design will be led by InhibOx and will include the virtual screening, computational chemistry and design activities. Iterative designs and hypotheses will be based on results obtained from downstream WPs.
WP3: Chemistry will be led by OSI and will contain FBDD, medicinal chemistry, organic synthesis and patentability studies. Molecular design and synthesis in WP2-3 will be the source of compounds for the downstream WPs. Importantly, starting points for the project will be provided by already available aaRS inhibitor compounds, which will be used for validation of hypotheses and assays.
WP4-7: have been carefully planned to contain incrementally increasing levels of complexity and cost, so that only those compounds showing pre-defined activity profiles will progress at each stage. Results will be carefully analyzed for the establishment of new hypotheses and for further compound design. WP4: Compound primary evaluation will be led by Omnia and will contain initial screening activities where inhibition of aaRS enzymes and bacterial growth inhibition will be tested. Initial screening activities will use S. aureus and E. coli as model organisms but other important pathogenic species will be assessed in the downstream WPs.
WP5: Compound secondary evaluation will be led by UNIVLEEDS and will include the evaluation of MoA, resistance and initial efficacy studies in animal models of infection.
WP6: Predictive therapeutic assessment will be led by EMC and will evaluate the compounds regarding their activity in clinical isolates. A characterization of the mechanisms of resistance will also be provided, and the possible synergistic effect of combination of the compound with other antibacterials will be explored. WP6 will also study the effect of the most promising compounds on bacterial metabolism through advanced mechanistic studies.
WP7: Compound characterization will be led by Omnia and will provide an advanced characterization of the most promising compounds in terms of oral drug-like properties and predicted toxicity. Compound activity in biofilms and complex models of infection, will be assessed and the effect of stringent response caused by aaRS inhibitors will be studied.