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INTEGRATE Report Summary

Project ID: 642620
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - INTEGRATE (Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets)

Reporting period: 2015-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

Antimicrobial resistance is posing a continuously-rising threat to global health. Indeed, one key recommendation from the recent “Action plan against the rising threats from Antimicrobial Resistance” report (submitted by the Commission to the European Parliament and Council (15.11.2011)) is the development of effective antimicrobials or alternatives for treatment of human and animal infections. The INTEGRATE project is a direct response to this. We have assembled a team of ten beneficiaries from eight EU member states, encompassing both academic and nonacademic sectors and different disciplines, to form a consortium committed to training Early Stage Researchers (ESRs) in the discovery and preclinical validation of novel Gram-negative antibacterial agents and antibacterial targets. The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure will be accomplished through a concrete secondment plan, coupled with a series of high-level consortiumwide training events and networking programmes. Our intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.

The description of action of the Grant Agreement foresees four main objectives for the project.
1) Identifying and optimizing novel chemotypes (chemical probes & validated hit compounds);
2) Establishing new tools and resources for antibacterial drug discovery (such as molecular models,
biological assays, animal models);
3) Validating non-canonical targets for combating Gram-negative bacterial infections (new strategy);
4) Strengthening inter-sectorial and multidisciplinary collaboration towards discovery of new antibacterial agents.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

INTEGRATE is an interdisciplinary training network aiming at growing a new generation of scientists focused on the discovery and validation of potential drug leads towards a set of still unexploited targets and pathways relevant for Gram-negative bacteria. This network responds to one of the most compelling threats for the human health, namely the resurgence of multidrug resistant bacterial infections. To accomplish this ambitious aim, INTEGRATE has gathered together ten European partners, from both the academic and non-academic sectors, covering a wide range of disciplines, from computational and synthetic medicinal chemistry, to biochemistry and in vivo microbiology. Recruited ESRs are supposed to exploit this interdisciplinary and intersectorial environment through an organized secondment scheme, where each ESR will be involved in a disciplinary activity and in a sector complementary to her/his main commitment. Through this, INTEGRATE wish to contribute to overcoming the fragmentation of approaches that often characterize drug discovery and to training the ESRs to go beyond methodological boundaries
between disciplines. The training-through-research part of INTEGRATE is focusing on a discrete set of gram-negative targets, not yet exploited clinically, for which we intend to clarify their potential relevance in the bacterial fitness, and for which we intend to progress a series of small molecules lead candidates for further development. The training-through-research plan is flanked by an active program of soft-skill acquisition and by a dissemination plan to increase the general awareness on the importance of basic research to fight bacterial infections.
The present report covers the activities carried out by the consortium in the period January the 1st, 2015 to November the 1st, 2016.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The contribution of the INTEGRATE the expected impact continues to be very relevant. The need for new approaches to the discovery of gram-negative antibacterials is still highly pressing. Newer case of superbugs are continuously reporting and there is a strong consensus that only multidisciplinary approaches will help tackling the threat. Furthermore, over these 24 months, synergies with other EU funded projects (such as TRANSLOCATE or the IMI ENABLE projects) have been identified. Their exploitation will maximize the impact of the EU funded research in the field of antibacterials.

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