The European Regimen Accelerator for Tuberculosis (ERA4TB) has the explicit goal of developing a new combination therapy to treat all forms of TB starting from ~20 leads and drug candidates provided by EFPIA. Since details of these are as yet unavailable, we will implement an agile drug development algorithm that entails profiling and portfolio construction. Profiling involves characterisation and ranking molecules in preclinical studies comprising in vitro drug combination assays, hollow fiber and single cell analysis, innovative murine and non-human primate models, PK/PD studies, combined with biomarker discovery and non-invasive NIR or PET/CT imaging to monitor disease progression and response to treatment. Modelling, simulation and artificial intelligence tools will help progress compounds from early preclinical to clinical development and to predict drug exposure, human doses and the best combinations. After extensive preclinical profiling, selected compounds will enter portfolio development for first time in human tests and phase I clinical trials in order to ensure that they are safe, well-tolerated and bioavailable with negligible drug-drug interactions. If needed, formulation studies will be conducted to improve pharmacological properties. ERA4TB has assembled the best expertise and resources available in Europe, to build a highly effective and sustainable drug development consortium with a flexible and dynamic management system to execute the profiling and portfolio strategy, aided by clearly defined go/no-go decision points. The expected outcome of ERA4TB is a series of highly active, bactericidal, orally available drugs to constitute two or more new combination regimens with treatment-shortening potential ready for Phase II clinical evaluation. These regimens will be compatible with drugs used to treat common comorbidities, such as HIV-AIDS and diabetes, and should impact UN Sustainable Development Goal 3, namely, ending TB by 2030.

The aim of Natalion is to foster innovation excellence of LIOS by the establishment of the Natural Products Research (NPR) group and implementation of the LIOS Innovation Hub as a complementary structural change. The introduction of new research strands and the structural changes will be achieved under the leadership of ERA Chair holder Dr. Stefano Donadio, an experienced Research and Innovation (R&I) professional. Project objectives: O1 Establishment of the NPR group, including its capacity build-up; O2 Setting up the research directions of the NPR group with a focus on new technologies and products; O3 Integration of activities of the NPR group into internal and external collaborative projects including 3I mobility; O4 Increase competitiveness for attraction of external research funding; O5 Establishment of the LIOS Innovation Hub and its integration into institutional, national and EU ecosystems; O6 Development of a motivating and inclusive institutional environment which fosters innovations and entrepreneurial culture; O7 Enabling institutional compliance to ERA priorities and UN Sustainable Development Goals; O8 Dissemination and exploitation of the results of the NPR group according to PEDR and a communication plan; Establishing the NPR group, the international recruitment, as well as the development of environment, fostering innovations will nurture brain circulation for researchers and innovators. The establishment of the LIOS Innovation Hub and its integration into institutional, national and EU ecosystems will deliver institutional reforms with a focus on innovation. Setting up new research directions and integrating the NPR group into internal and external collaboration networks under the competent guidance of the ERA Chair will leverage excellence of R&I and increase the competitiveness for attraction of external research funding. Better communication of R&I results to society will be achieved by Dissemination and Exploitation of the project results.

The gap in Research and Innovation (R&I) performance, which persists despite considerable investments from the European Structural and Investment Funds (ESIF) in the lower-performing regions of the EU, is an issue with major socio-economic and political consequences. In Health R&I the gap has a profound impact on distribution of funding from the EU Framework Programmes as well as on hindering the EU-wide impact of R&I on health and quality of life. With A4L_ACTIONS, we aim to address roots of this situation in the lower-performing Central and Eastern Europe (CEE) by improving culture, governance, recognition and innovation potential of the health research-performing institutions. Our goal is to increase their attractiveness for collaborations with advanced Europe and create spill-over effects in the whole region. As the Alliance4Life, we are an established network of progressive health research institutions in CEE and a source of successfully piloted good practice. By building upon our results and impact achieved so far, we will convert our recommendations and strategies into actions as follows: - Culture fostering excellence: piloting peer-evaluation and assessment of institutional practice as a strategic management tool, professionalizing research administration; - Recognition and trust towards CEE: attracting advanced partners to identified pockets of excellence, supporting scientific ideas originating in CEE, initiating new international projects and collaborations with industry; - Career policy nurturing talent: training and networking next generation of leaders, upgrading institutional career systems; - Impact on innovation: raising the competences of Technology Transfer specialists, creating industry relations platform linking academia and industry; - Spill-over effects: sharing, inspiring, communicating with stakeholders and policy makers; using the established networks to gain advice, new collaborations and EU-wide impact.

The discovery of penicillin initiated the antibiotic era and saved millions from dying of life-threatening bacterial infections such as tuberculosis, sepsis, and pneumonia. Penicillin kills bacteria by inhibiting synthesis of peptidoglycan, an important structure of the bacterial cell envelope. Still today, antibiotics targeting the bacterial cell envelope are the most widely used antibiotics in the world. Unfortunately, resistance to these superior antibiotics is becoming highly prevalent and antibiotic-resistant bacteria represent one of the greatest threats to human health and development today. In the CLEAR (Cell Envelope Anti-bacterials) training network, world-leading researchers from academia have gathered with clinicians and 4 highly relevant SME partners to train a new generation of excellent European scientists in finding novel solutions for targeting the cell envelope of bacteria, who know how findings in academia generate assets to SMEs, and who could bring novel antimicrobial solutions to the market. The proposed research program builds on unique findings of the project partners that allow us to take up innovative and yet feasible approaches 1) to identify novel targets in the cell envelope and to evaluate the lead structure potential of novel agents acting on the cell envelope, 2) to re-sensitize resistant bacteria to existing cell wall antibiotics, 3) and to explore novel therapies acting via the cell envelope. Impacts of this proposal are the re-use of safe and cheap antibiotics, and the drugs already approved for treatment of other diseases as novel antimicrobials. The training program combines a broad range of scientific disciplines such as molecular biology, biochemistry, structural biology, screening technologies, pre-clinical testing with complementary courses in innovation, market potential and business strategies ensuring that the 10 PhDs will be highly competitive for both top European research institutions and the pharma/biotech job market.

The candidiasis disease is one of the more severe fungal infections with particularly high mortality amongst immunocompromised patients. It is caused by the opportunistic fungus Candida albicans (C.albicans) that is quite resistant to common antifungal medicines. The cell wall of C.albicans has a key role for protection and interaction of fungus, making it a promising target for new antifungals. However, the structural organization at atomic level for the intact C. albicans cell walls remains understudied. Here we are proposing a project, which will focus on the cell wall molecular organization studies at atomic level for the intact C. albicans fungus using non-destructive solid-state nuclear magnetic resonance (ssNMR) spectroscopy. We will elucidate the intact C.albicans cell walls by exploiting modern 1H and 19F detected ssNMR technologies at fast magic angle spinning regime. During this interdisciplinary project we plan to improve the selective 1H, 13C, 15N labeling schemes and create a novel biochemical 19F incorporation in the C.albicans cell walls. In combination with development of new 1H and 19F detected ssNMR techniques, we will elucidate the structures of main polysaccharides, lipids and proteins, allowing to decipher the supramolecular arrangements. The anticipated findings in this research project will provide a precise structural model of the intact C.albicans cell walls, paving a way for discoveries of new antifungals.