AMR-TB · Theoretical and computational investigation of tuberculosis antimicrobial resistance development based on extensive experimental library of mycobacterium strains

Theoretical and computational investigation of tuberculosis antimicrobial resistance developmentbased on extensive experimental library of mycobacterium strains

Tuberculosis (TB) is a global pandemic disease, one of the top 10 causes of deaths worldwide. Almost one third of the world's population is latent carriers of TB bacteria. Although TB is usually curable, its modern strains often exhibit multi-drug resistance which makes TB a lethal threat; the number of such cases constantly grows (currently estimated by the World Health Organization (WHO) as 480 000 people worldwide and counting). To overcome this challenge, the unified effort of specialists in different branches of fundamental and clinical sciences is required. Antimicrobial resistance (AMR), the ability of microorganisms to overcome almost all of the antimicrobial treatments that we currently have, has been identified as one of the main challenges facing the 21st century, and it has become a critical problem across the globe, including in the developed world. Unless we step up our research efforts and find new approaches to deal with these bugs, it might not be long before we will find ourselves in a situation similar to times before the development of the penicillins, where simple infections turn out to have deadly consequences. Isoniazid (INH) is the main and historically one of the first drugs used for TB treatment. Our goal is to understand the mechanism of the interaction between the catalase KatG and INH and the cascade of biochemical processes resulting in the bacterial death. We will investigate how mutations in KatG influence the stacking in the active centre of enzyme and drug metabolism. Using this knowledge we will suggest possible modifications of the drug for treating tuberculosis. The specific objectives of the project consist of the following. The research objectives of the RISE project are: 1. The determination of minimal inhibition concentration of INH to 100 strains of M. tuberculosis with a wide spectrum of drug resistance (WP2). 2. Genome sequencing of the 100 strains obtained in objective 1 (WP1). 3. The molecular genetics and recombinant protein production of wildtype and mutant KatG orthologues based on the data obtained in objective 1 and 2 (WP1, WP3, WP4). 4. The investigation of enzymatic activity of KatG for various strains obtained from patients with AMR to INH (determined in objective 3) (WP2). 5. Using results of objective 4, the investigation of the catalase structure and its mutants and the creation of the genotype-phenotype map and fitness landscape of the bacterial strains (WP1). 6. Mathematical modelling of the metabolic pathway of INH transformation in the bacterium (normal and mutant) elucidated in objective 4, the prediction of the metabolic pathway at different mutations (WP3). 7. High performance molecular dynamics simulations of the interaction of INH and catalase based on the molecular structures obtained in objective 5 (WP1, WP2). 8. Studying the native dynamics of catalase using normal mode analysis for deducing the mechanisms of INH-KatG interaction, complementing and making more accurate the results of objectives 5 and 7 (WP2). The knowledge transfer objectives (KTO) of the RISE project are: 1. To develop and strengthen research and innovation partnerships (i.e. joint research programme and co-supervision of research students) between the EU, Russia, Japan and Ecuador through international staff exchanges and networking activities (WP1-WP4). 2. To strengthen EU research and innovation through enhanced training, mobility and career development of experienced and early stage researchers (WP5, WP6). 3. To disseminate widely, and fully exploit the outcomes of the project through published articles, seminars, summer school, workshops, conferences and commercial exploitation opportunities (WP5). 4. To fully embrace public engagement to communicate the research activities with the public (WP5). 5. To work towards the sustainability of the collaboration through the development of project proposals for further funding (WP6). 6. To effectively manage the Research and Innovation Staff Exchange programme for maximum knowledge exchange and career development for all the researchers (WP6).

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