Antimicrobial resistance (AMR) is a challenge to human health and health-systems, and we need novel antimicrobials or drugs that can re-sensitize multi drug resistant (MDR) bacteria to existing antimicrobials. Metabolic enzymes have largely been ignored in the search for antimicrobial targets, and they are an untapped resource. The aim of INNOTARGETS is to train ESRs in highly innovative approaches to identify metabolic drug targets in pathogenic bacteria. The training will deliver ESRs that can become creative, future research team leaders within industry or academia. The network joins 7 academic and 3 non-academic organisations, including two antibiotic discovery companies. The training is multi-disciplinary and trans-sectoral and provides 432 person-months of training to 12 ESRs. The types of targets foreseen are: 1) Metabolic enzymes that are essential for infection, Such enzymes will be identified by use of transposon libraries 2) Redundant enzymes, which can be blocked in parallel. Relevant pairs of enzymes will be identified by use of metabolic models, and a search for bioactive molecules, with affinity for more than one target will be carried out using a novel screening platform. 3) Metabolic enzymes which are essential for expression of resistance mechanisms or spread of resistance plasmids in MDR bacteria. Putative targets for all three types of reactions will be validated using cell culture and animal models. INNOTARGETS will establish a joint training syllabus designed to widen the career prospects of the ESRs and to optimize their professional competences. It includes training through research, including secondments, network wide training courses and summer schools, self-directed learning, workshops and training through interaction with external partners and visiting scientists.

Antimicrobial resistance, which is caused by multi-drug-resistant bacterial pathogens is a global health emergency. Gram-negative bacteria (GNB) notably hinder effective treatment because of their impermeable outer membrane (OM). Consequently, many standard-of-care (SOC) antibiotics cannot access intracellular targets in GNB. The objective of the BREAKthrough European Training Network (ETN) is to sensitise GNB to these antibiotics by making their OM permeable. To this end, we will develop inhibitors of three protein machineries that are responsible for OM maintenance. Importantly, many known antibacterial agents have characteristics different from drugs that are directed against targets in mammalian cells. To define better rules for antibacterial drug development a data hub will be created to assemble information on the physico-chemical characteristics of molecules that can pass the OM. To achieve these goals, a multi-disciplinary academic-industrial consortium has been assembled with organic chemists, computational chemists and specialists in high-throughput drug screening, zebrafish infection models, bacterial morphogenesis and the molecular biology of the three targets. The expected outcomes of the BREAKthrough ETN include (i) the development of new chemical space rules for drugs that need to cross the OM, (ii) the discovery of new inhibitors that interfere with OM maintenance to overcome the insensitivity of Gram-negative pathogenic bacteria towards SOC antibiotics and (iii) providing 10 Early Stage Researchers with scientific, technical, business and transferable skills to become professional drug developers with a keen eye for the hurdles in the development of these drugs in an industrial context.