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Projects / Programmes source: ARRS

Preclinical development of new antibacterial drugs

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Research activity

Code Science Field Subfield
1.09.00  Natural sciences and mathematics  Pharmacy   

Code Science Field
B740  Biomedical sciences  Pharmacological sciences, pharmacognosy, pharmacy, toxicology 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
Drug Discovery, Antibacterial Drugs, Computer Aided Drug Design, Synthesis of New Drugs, Resistance to Antibiotics, Enzyme Inhibitors, X-ray Crystallography.
Evaluation (rules)
source: COBISS
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (14)
no. Code Name and surname Research area Role Period No. of publications
1.  25434  PhD Urban Bren  Natural sciences and mathematics  Researcher  2011 - 2014  326 
2.  15284  PhD Stanislav Gobec  Natural sciences and mathematics  Principal Researcher  2011 - 2014  801 
3.  02287  PhD Milan Hodošček  Natural sciences and mathematics  Researcher  2011 - 2014  279 
4.  32036  PhD Martina Hrast Rambaher  Natural sciences and mathematics  Researcher  2011 - 2014  110 
5.  06734  PhD Dušanka Janežič  Natural sciences and mathematics  Researcher  2011 - 2013  493 
6.  01463  PhD Danijel Kikelj  Natural sciences and mathematics  Researcher  2011 - 2014  561 
7.  30698  PhD Jakob Kljun  Natural sciences and mathematics  Researcher  2014  164 
8.  25435  PhD Janez Konc  Natural sciences and mathematics  Researcher  2013 - 2014  225 
9.  04648  PhD Janko Kos  Biotechnical sciences  Researcher  2011  1,137 
10.  29341  PhD Vita Majce  Natural sciences and mathematics  Researcher  2012 - 2014  37 
11.  28861  PhD Stane Pajk  Natural sciences and mathematics  Researcher  2011  171 
12.  30816  PhD Izidor Sosič  Natural sciences and mathematics  Junior researcher  2011  227 
13.  29773  PhD Samo Turk  Natural sciences and mathematics  Researcher  2011 - 2013  88 
14.  28905  PhD Nace Zidar  Natural sciences and mathematics  Researcher  2011 - 2012  204 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,119 
2.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  16,356 
Abstract
As society has become increasingly dependent upon antibiotics, the selection pressure for emergence of resistant bacterial strains has increased, and so-called antibiotic-resistant ‘superbugs’ are now a major global health problem. The development of resistance can interfere with, or even prevent, the treatment of bacterial infections, especially in hospitals. New drugs are urgently needed to provide doctors with fresh options to treat these infections. We intend to discover new inhibitors which will attack the formation of bacterial peptidoglycan, and this will either kill the bacteria directly or make them more susceptible to existing antibiotics. Peptidoglycan is a macromolecule which is essential for and specific to the bacterial cell wall. The numerous enzymes involved in its biosynthetic pathway constitute potential targets for the discovery of new antibiotics. To identify novel lead compounds that are important for antibacterial drug discovery, we will target the selected enzymes that catalyze the intracellular stages (Mur ligases MurC-F and DdlB) and extracellular stages (the penicillin-binding proteins) of peptidoglycan biosynthesis. Strategies for inhibitor discovery will be based on the available X-ray crystal structures and will involve sophisticated computational techniques, like de novo structure-based inhibitor design and virtual high-throughput screening, and chemical synthesis of libraries of potential inhibitors and their biochemical (evaluation of inhibitory activities), structural (determination of X-ray crystal structures) and antimicrobial (determination of MIC values) evaluation. It is intended to discover several structurally distinct lead molecules with micromolar or nanomolar inhibition of target enzymes and with antimicrobial activities. The strength of this project includes (1) the multi-targeted approach that involves enzymes from a variety of pathogenic species, and (2) the vast number of techniques employed, provided by the different types of highly complementary expertise of all partners incuded. The group of the partners from Slovenia is specialised in computational drug discovery methods like virtual high-throughput screening and de novo molecular design, medicinal chemistry and synthetic organic chemistry, while other international partner groups are specialised in bacterial peptidoglycan biosynthesis enzymes expression and purification, biochemistry, microbiology and X-ray crystallography. During the previous collaboration with international partners and Slovene pharmaceutical company Lek d.d. we have developed a series of promising inhibitors of bacterial peptidoglycan biosynthesis enzymes and this work will be countinued during this project. Lead compounds identified in this project will represent very important steps towards the development of new broad action antibacterials that will be of key importance in the fight against emerging bacterial resistance. The results will be published in high-ranked journals and international patent applications. Involvment of industrial partner will allow for the transfer of knowledge to the Slovenian pharmaceutical industry. The leader of the proposed project and team members have demonstrated with their research achievements that the project is feasible and that all required equipment is available. The proposed project will take advantage of the existing network of international collaboration, which has been created during the FP6 project EUR-INTAFAR, coordinated at the Faculty of Pharmacy by Professor Stanislav Gobec (collaboration with universities of Paris, Leeds, Liege, Warwick and Institute of Structural Biology in Grenoble). In addition, the leading experiences of Professor Stanislav Gobec (Vice-Dean of the Faculty of Pharmacy 2005-2007, Dean of the faculty 2007-2011) assure good leading of the proposed project.
Significance for science
Importance of the proposed research project for the development of science resides in (i) discovery of novel drugs in important therapeutic area and in (ii) development of methods for drug design, synthesis and study of their molecular mechanism of action. The research project provided an important contribution to discovery of innovative antibacterial drugs with novel mechanisms of action. Discovery of novel antibacterial drugs is a great challenge to science due to a threatening bacterial resistance to currently used antibacterial drugs. Within the research project, important drug discovery tools were used and developed in close collaboration with Slovene and international partners: - Rational design and synthesis of new potential drugs, - Computational methods for structure-based virtual high-throughput screening, - De novo design of new enzyme inhibitors, - Development and optimisation of new synthetic methods, - Development of simple and rapid methods for biochemical evaluation of enzyme inhibitors (drug candidates), - Resolution of crystal structures of bacterial enzymes in complexes with their inhibitors. A special attention was devoted to the application of the abovementioned tools in the field of antibacterial drug discovery. With the development of small molecule non-covalent inhibitors of peptidoglycan we were able to obtain new lead compound inhibitors with antibacterial activity.
Significance for the country
Research and development of novel drugs is a way to assure a sustained growth to Slovenian pharmaceutical industry, which is currently one of major players in the Slovenian economy. The knowledge about discovery of new antibacterial agents relevant for this project is important both for innovative and generic pharmaceutical industry. Researchers, which participated in the proposed research project, have gained competences for autonomous creative work in pharmaceutical industry, where they will create novel research focuses in the future. They have been also perfectly trained for research work at the university, other research institutes and governmental agencies. The proposed research programme has generated new and mastered the existing knowledge both of which are of paramount importance for sustained development of pharmaceutical industry and drug – oriented research in Slovenia. The proposed research project has created important new knowledge in fight against bacterial resistance. This has the potential to contribute to global reduction of nosocomial infections which represent enormous economic burden to health-care systems. The scientific excellence, achieved during the proposed research project, has contributed to affirmation of Slovenian science through publications in leading scientific journals. This has contributed to creation and preservation of the country's national identity in Europe and in the world. The results of the research project were published in high-ranked international journals with SCI Impact Factor and international patent applications. The results were also presented on international scientific conferences. This has contributed to international affirmation of Slovenia and Slovenian science. The research project enabled the collaboration between two most important Slovene research institutions that are active in the field of pharmaceutical sciences: Faculty of Pharmacy from the University of Ljubljana and Chemical Institute. The research project has enabled researchers from Slovenia to visit the esteemed foreign institutions (University of Warwick, University of Leeds, and University of Paris, University of Liege, Institute of Structural Biology in Grenoble). This has enabled the transfer of knowledge in the fields of structure-based drug discovery, de novo design of enzyme inhibitors, molecular modelling, protein crystallography, and enzymology, to Slovenia. The fact that the research project has been performed at the Faculty of Pharmacy, University of Ljubljana, has enabled the researchers to be in constant contact with both undergraduate and postgraduate students. This has enhanced the quality of research work of students, their development and their employment opportunities as well as the quality of teaching at the Faculty.
Most important scientific results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
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