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INTPART-International Partnerships for Excellent Education and Research

Reversing antimicrobial resistance

Alternative title: Kampen mot antimikrobiell resistens

Awarded: NOK 4.5 mill.

Antimicrobial resistance (AMR) is emerging as a major global threat to health care. This situation has escalated globally and in Norway in the last years. We are implementing a unified INTPART approach for research-based education on innovative preventive and therapeutic measures along with development of novel diagnostics and drugs to combat AMR. The AMR-PART project addresses the nature and role of chromosomally mediated antibiotic resistance with Mycobacterium tuberculosis (Mtb) and Neisseria gonorrhoeae (Ng) as model organisms. Tuberculosis (TB) is one of the top 10 causes of death worldwide. This emerging and devastating microbial disease was in 2019 reported to be the cause of 9 million newly-diagnosed cases and 1.5 million deaths. TB, caused by Mtb, represents an increasingly serious challenge to public health, due to recent emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains. The incidence of TB and gonorrhea is re-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 bacterial variants, selected by overuse of antibiotics. As antibiotics apply a selective pressure, we postulate that hypermutating strains are likely to emerge under this stress, perpetuating the selection of MDR- and XDR-strains. Results on the AMR-PART objectives in 2017-19: We have developed a unified research-based education approach to support novel diagnostics and drugs to combat AMR. AMR-PART is thus testing the hypothesis that sub-inhibitory concentrations of antibiotics trigger mutagenic processes inducing chromosomally mediated drug resistance. The advanced research-based and innovative educational track-record and results are fully in line with and support UN sustainable development goals # 3, 4, 8, 9 and 17. 1) To establish a collaborative international education, research and innovation program, linked to and building on sustainable new and long-term educational programs. The AMR-PART partnership is formed by strong research groups in Norway with complementary and multidisciplinary expertise teamed up with outstanding international collaborators in South Africa, the United States and China. New training has been built for each step of the experimental plan to reach the defined AMR-PART goals. We are thus building a comprehensive set of educational tools facilitating knowledge on AMR and bacterial evolution. The research-based education is already facilitating novel diagnostics and novel intervention over-riding AMR, as well as capacity building and frontline research-based sustainable education. The new courses have CME approval at 2 faculties at UiO and in collaborating institutions for higher education. 2) To identify gene targets that drive antimicrobial drug resistance development. AMR-PART has convergently employed functional genomics/ transcriptomics/proteomics and bioinformatics, genetics and biochemical approaches to delineate AMR responses in Mtb and Ng. We have discovered that specific defects in Mtb replication and genome maintenance induce increased mutagenicity. We have also discovered that AMR targets exhibit signatures in that they are decorated by post-translational modifications (so-called PTMs). 3) To search for novel drugs against multi-drug resistant bacteria by following selected hits and leads for new antimicrobial drugs, with new concepts and tools for drug discovery. We are continuously searching for novel components induced under sub-inhibitory antibiotics-stress as potential drug targets. Mtb and Ng mutant libraries have been constructed and component collections are currently being screened in combination with rational drug design to discover novel inhibitors. We have tested novel drug derivatives for improved efficacy, and have 2 new hits. Hits identified through these screens are being characterized with regard to their mechanism of action. A new vaccine against multiresistant TB is ready for testing. Capacity building and dissemination: The AMR-PART project is a multidisciplinary endeavour that engages scientists from complementary fields of research in a unified action to combat AMR. In addition to organizing AMR-PART conferences and workshops in 2017-2019, where all partners presented their work, we have provided diagnostics, molecular and bioinformatics training for representatives from Ethiopia. The molecular studies and advanced training have resulted in capacity building and technology transfer between industrial and LMIC countries in Africa. AMR-PART has also had ample public dissemination activities by running AMR blogs, podcasts and presenting at Forskningstorget 2019. The successful outcome of the INTPART phase 1 funding for AMR-PART is evidenced in the advanced research-based and innovative educational track-record and publications, supporting UN sustainable development goals # 3, 4, 8, 9 and 17.

Outcomes While the AMR crisis currently is escalating, main AMR-PART outcomes are: 1) new interdisciplinary international research collaborations, 2) new research-based educational courses, 3) existing education more sustainable, and 4) young scientists and students have expanded their research networks. The new courses and workshops in translational research as they have unleashed synergies between strong basic science environments and clinical medicine. Impact The AMR-PART efforts have provided a unique, interdisciplinary platform for education and training of future clinicians and basic scientists. These measures will enhance recruitment to the field, generate better opportunities for collaboration and greater access to funding. AMR-PART has contributed to increased quality in AMR education and research. AMR-PART has further heightened the awareness of AMR in society, providing a setting conducive to reduction of antbiotics use and implementing policies to reduce antibiotics use.

Antimicrobial resistance (AMR) is emerging as a major global threat to health care. We propose a unified INTPART approach for research-based education in innovative preventive and therapeutic measures along with development of novel diagnostics and drugs 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 collaborators in South Africa and China. The AMR-PART project addresses the nature and role of chromosomally mediated antibiotic resistance with Mycobacterium tuberculosis (Mtb) and Neisseria gonorhoeae (Ng) as model organisms. Tuberculosis (TB) affects 1/3 of the world's population. The incidence of TB and gonorrhea is re-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 variants of Mtb and Ng, namely antibiotic treatment. As antibiotics apply selective pressure, we postulate that hypermutating strains are likely to emerge under this stress, perpetuating the selection of multidrug-resistant and extensively drug-resistant strains. Consequently, components induced under antibiotics-stress will be investigated as potential drug targets. Mtb and Ng mutant libraries will be constructed and component collections will be screened in combination with rational drug design to discover novel inhibitors. Hits identified through these screens will be characterized for their mechanism of action. Advanced courses 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 and bacterial evolution. 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