Antibiotic resistance (AMR) is a major public health issue, with 5 million deaths in 2019 linked to AMR worldwide. These numbers are comparable to the toll of the SARS-CoV-2 pandemic. Without new solutions, AMR is projected to soon become one of the leading causes of death in the EU. Addressing this challenge requires the development of new, effective antibiotics, but this alone is not sufficient due to the rapid evolution of bacteria. Understanding the drivers and mechanisms of AMR is vital to delay or reverse resistance in both existing and new antibiotics, especially since no new broad-spectrum antibiotics have been developed since the 1990s and their development is a lengthy process with high attrition rates. The ENDAMR doctoral network aims to better equip researchers in Europe to understand and develop new strategies to tackle AMR. WP1 focuses on how AMR affects the fitness of pathogenic bacteria in the gut microbiome, aiming to identify microbiome characteristics that predispose to AMR infections and to explore microbiome-based interventions. WP2 examines AMR acquisition via horizontal gene transfer, investigating evolutionary pathways, host genetics, environmental factors, dissemination, and AMR reservoirs. WP3 is dedicated to understanding the frequency, mechanisms, and clinical implications of antibiotic resistance, with a particular focus on the less studied aspects of heteroresistance and tolerance, and to developing diagnostic tools and predictive models. WP4 explores the combination of antibiotics to enhance treatment outcomes and potentially prevent or reverse AMR, based on understanding the interplay of resistance mechanisms. ENDAMR will also prepare doctoral candidates for various career paths beyond academia, including teaching, science communication, and entrepreneurship. Candidates will gain transferable skills and learn from industry role models, equipping them to make significant contributions to solving the AMR crisis.

Algae4IBD's mission is to develop commercial products for Inflammatory Bowel Disease (IBD) prevention and treatment using aquatic natural biological resources. With the emerging developments in natural product, notable success has been achieved in discovering natural products and their synthetic structural analogues with anti-inflammatory activity. However, global biodiversity remains a largely unexploited resource for natural bioactive molecules with an enormous potential for developing commercial products with public health benefits. Micro and macroalgae, found in marine and freshwater, have been identified as promising sources of bioactive compounds including small molecules and secondary metabolites with a wide range of bioactivities as an antioxidant, anti-inflammatory and cancer preventive. Consumption of algae could, therefore, provide defence against chronic inflammatory diseases such as IBD, that until date have no effective cure. This project offers nature to bedside approach, using an entire development along the value chain for a new biodiscovery therapeutic approach by developing and examining algae-based compounds for IBD patients while guaranteeing algae's biodiversity preservation. We propose innovative solutions for increasing the use of algae-based ingredients and to ensure the science-based improvement of nutritional quality and its effect on public health. The researchers, companies and hospitals involved in the different stages of the project will use the biodiversity of algae, both micro and macro, as a wide source for bioactive compounds using state-of-the-art cultivation and extraction technologies for obtaining sufficient amounts of the bio-active molecules together with novel processing protocols. It will result in novel algal-based, high-quality bioactive compounds at GMP grade and lower costs for dual purposes – IBD prevention and treatment in relevance to the food as well as the pharmaceutical industries.

In this project, we aim to study the genetic mechanisms of convergent evolution by uncovering the mechanistic details of two highly replicated transitions in organismal complexity. Convergent evolution is widespread in nature, even on macroevolutionary timescales. To explain its pervasiveness, recent studies have proposed the idea of predisposing precursor traits that, if easily co- or exapted for new functions, can increase the likelihood of convergence. However, most of these hypotheses remain untested because of the lack of tractable model systems. We identified two fungal case studies that offer optimal model systems to mechanistically test the hypothesis that precursor traits increase the likelihood of convergence: (i) 8-11 repeated origins of complex multicellularity in mushrooms and (ii) >14 losses of multicellularity in yeast-like fungi. We hypothesize that both of these occurred by the repeated exaptation of ancient morphogenetic programs and, in the case of yeasts, additionally, by the emergence of mechanisms for bypassing multicellular growth. Our hypotheses imply that both complex multicellular and yeast-like lifestyles are only a few mutations away for any filamentous fungus because precursor traits shorten the mutational path for evolution. Although these are bold hypotheses, we obtained promising preliminary results that support them. We designed an experimental plan involving phylogeny-aware comparative -omics, reverse genetics, and evo-devo, which, when combined with our preliminary results, will provide a robust entry point for testing the role of predisposition in convergent evolution and will ultimately allow us to “replay the tape of major fungal transitions” in the laboratory. We expect this project to contribute to uncovering the general principles of convergent evolution and to be one of the first to mechanistically test if certain precursor traits can promote convergence.

Microbiota medicine is the new frontier in human health. The human gastrointestinal tract is home to trillions of microbes. Under normal conditions, these microbial communities drive physiological and homeostatic functions in the host; when altered, they can lead to severe disorders. With an increasingly recognized role in health and disease, the gut microbiota offers promising therapeutic and diagnostic potential to tackle various pathologies (incl. metabolic, neurological, and cardiovascular disorders). Its full clinical potential remains largely unrealized though, mostly due to the lack of critical mass capable of integrating the multiple scientific and translational dimensions of microbiota medicine. Grounded on a team of 180leading researchers and entrepreneurs from across 12 countries and dispersed disciplines (biological big data analytics, systems and synthetic biology, experimental and translational medicine), MiCCrobioTAckle will train 12 Doctoral Candidates (DCs) with the much-needed cross-disciplinary and -sectoral expertise to advance microbiota medicine. As course-setting disease, the DCs will focus on cancer cachexia (CC). CC is an excellent model to study the host-microbiota axis in the context of metabolic diseases and represents the paradigm of a devastating condition in urgent need of new and more efficient means of clinical management. Along MiCCrobioTAckle, the 12 high-calibre DCs will foster new discoveries with impact on CC, while driving scientific and technological progress in microbiota medicine in its broadest scope. By training the next generation of researchers with out-of-the-box thinking and an entrepreneurial mindset in microbiota medicine, MiCCrobioTAckle will safeguard the EU leadership in this vanguard and imperative biotech/pharma segment, while paving the way for the development of novel gut microbiota insights and tools to tackle multiple diseases with foreseeable impact on the well-being of billions of citizens worldwide.

Although several new antibiotic candidates are in the clinical pipeline, the future evolution of resistance in bacteria may render them ineffective. This project aims to develop a framework for forecasting the long-term effectiveness of new antibiotic candidates. For this purpose, we will decipher the general principles shaping bacterial resistance to a wide range of antibiotic candidates currently in development. Using recently developed methods in our laboratory, we will study resistance evolution in bacterial ESKAPE pathogens at unprecedented resolution and address four specific aims. First, we explore the shared features of antibiotics with limited susceptibility to resistance. Second, we systematically map species-specific differences in resistance evolution with implications on narrow-spectrum antibacterial therapies that could remain effective. Third, we assess the clinical risks associated with resistance by studying the global biogeography and habitat-specificity of resistant bacteria. Finally, we systematically explore the potential links between resistance evolution and increased bacterial virulence. The outcomes will provide guidelines for future antibiotic use, aid in genomic surveillance of resistance genes, and facilitate the design of antibiotics with reduced susceptibility to resistance.