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INTPART-International Partnerships for Excellent Education and Research

Reversing antimicrobial resistance (AMR)

Alternative title: Reversering av antimikrobiell resistens (AMR)

Awarded: NOK 3.5 mill.

Antimicrobial resistance (AMR) is a global health threat, both in humans and animals. This situation has escalated globally and nationally in recent years, and has become one of the world's major pandemics. We have therefore developed an INTPART strategy with research-based teaching and advanced training to ensure innovative prevention, diagnostics and treatment to combat AMR. The World Health Organization (WHO) has created a prioritized list of the most important disease-causing microbes globally. Based on this list, the AMR-PART project has focused on antibiotic resistance, with the bacteria Mycobacterium tuberculosis (Mtb) as model organism. Tuberculosis (TB) is one of the 10 most deadly diseases worldwide. The bacterium that causes TB is found in approximately 1/4 of the world's population, and 10 million new TB cases are detected annually. The ongoing pandemic is being exacerbated by antibiotic-resistant variants, so-called multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains. To tackle these problems, we have performed research on how Mtb becomes resistant and can be treated. Since antibiotics exert a selective pressure, hyper-mutator strains will arise under stress, with the selection of multi-resistant MDR and XDR strains. The RevAMR project has completed its goals of: 1) establishing international cooperation for education, research and innovation, with the development of sustainable AMR education programs, 2) implementing innovative learning in the analysis of large data sets, by promoting machine learning and artificial intelligence, and 3) organize advanced courses and discovered new intervention against multidrug-resistant microbes. We have developed a set of very popular advanced bioinformatics courses to promote efficient and deeper analysis of genome sequences (DNA), as a basis for machine learning and artificial intelligence. We have also carried out practical training to promote proteomics analyses, at the protein level. We have completely new discoveries that show that modifications of macromolecules such as DNA, RNA and proteins impact on how antibiotics work and how antibiotic resistance develops. Increased understanding of the mechanisms that cause Mtb to become antibiotic-resistant is essential for improvement of current TB treatment. In the network we have developed and exchanged completely new components as well as derivatives of known medicines, in order to develop new antibiotics and repurpose known medicines in a new context. We have tested the effect of new phenazine derivatives in sensitive and resistant Mtb isolates. Our aim was to find out whether the phenazine derivatives worked in both reference strains and clinical Mtb isolates with different resistance patterns. The effect of the phenazine derivatives was analyzed by growth in vitro and detection of redox potential using Resazurin in the microtiter assay (REMA), as well as in various cell lines. We have thus discovered that the phenazine derivatives work well against the clinical Mtb isolates, including those that are resistant to other drugs. By discovering the effect of the drug on bioenergetics in the Mtb cell and the development of Mtb phenazine resistance, we achieved the goal to discover the mechanism of how the phenazine derivatives work in TB (proof of concept). Thus, new and even better phenazine derivatives can now be developed, with the optimization of current TB treatment into improved therapy that can be taken per-orally. The INTPART AMR project is an interdisciplinary collaboration that has brought together researchers and students from various fields in a joint effort against AMR. Top researchers from Norway (UiO), India (Indian Institute of Technology Indore), China (Zhejiang University and Nanshan CCDC Shenzen University) and South Africa (University of Cape Town) have been project participants with active research, teaching and training. Five students have defended their PhD on AMR mechanisms, with INTPART colleagues as opponents. To the extent that the corona epidemic has allowed, we have had an exchange of master's and PhD students. A lot of contact has been digital conferences, meetings and other online activities to ensure the great progress in the project. The last physical exchange was between Norway, India and South Africa where we actively contributed to the Nobel seminar on new TB treatment in Stellenbosch 2023. Together, the INTPART AMR team has created a solid foundation for lasting human capacity building and technology transfer, also between industrial countries and low-income countries. This research-based teaching strategy for new diagnostics, prevention and treatment to combat AMR is in line with the UN's Sustainable Development Goals #3 (Good health and quality of life), #4 (Good education), #8 (Decent work and economic growth), #9 (Industry, innovation and infrastructure) and #17 (Cooperation to achieve the goals).

RevAMR efforts have provided a unique, interdisciplinary venue for the education and training of future generations of clinicians and scientists in Norway, South Africa, India and China. These outcomes will undoubtedly enhance recruitment to the research field of infection biology and AMR, and generate better opportunities for collaboration and greater access to funding from national and international agencies. RevAMR research-based education has not only significantly contributed to the global effort to fight against infections by implementing understanding of AMR professionally and publicly worldwide, but it has also generated a better understanding of the molecular mechanisms related to AMR, and generated new avenues for treating AMR infections. Approximately ¼ of all health-related costs in the world are associated with infectious diseases. AMR is still a global priority and a major issue in society, and TB is the biggest bacterial killer worldwide. RevAMR outcomes are therefore likely to generate sustainable education, innovation and institutional spin-offs in new settings. AMR-PART thereby has responded to an urgent worldwide health crisis, most relevant to INTPART.

Antimicrobial resistance (AMR) is emerging as a major global threat to health care. The AMR challenge has escalated further the last 3 years. We propose a unified INTPART approach for research-based education in innovative preventive and therapeutic measures along with development of novel diagnostics to combat AMR. The AMR-PART partnership is formed by strong research groups in Norway with complementary and multidisciplinary expertise teamed up with outstanding international BRIC collaborators in South Africa, India, China and the US. The AMR-PART project addresses the nature and role of chromosomally mediated antibiotic resistance with Mtb and Ng as model organisms. Tuberculosis affects 1/3 of the world's population. The incidence of AMR is still emerging as a public health problem worldwide. The AMR-PART project builds on the hypothesis that the current epidemics are fuelled by the selection of adapted and resistant microbial variants, due to antibiotic treatment. As antibiotics apply selective pressure, we postulate that hypermutating strains are likely to emerge, perpetuating the selection of multidrug-resistant and extensively drug-resistant strains. Consequently, components induced under antibiotics-stress will be investigated as potential drug targets. Mutant libraries will be constructed and component collections will be screened in combination with rational drug design to discover novel inhibitors. Hits identified will be characterized for their mechanism of action. Advanced courses, workshops and training will be established for each step of the experimental plan required to reach these goals. The expected outcome will be a pipeline of educational tools facilitating knowledge on AMR, in line with UN sustainable development goals # 3, 4, 8, 9 and 17. The research-based education will facilitate novel diagnostics, drug targets and drug leads over-riding AMR, as well as capacity building and frontline research-based education in sustainable settings.

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INTPART-International Partnerships for Excellent Education and Research