Projects / Programmes
Combating bacterial resistance: optimisation of bacterial cell wall biosynthesis inhibitors
| 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 |
Drug Discovery, Antibacterial Drugs, Computer Aided Drug Design, Synthesis of New Drugs, Resistance to Antibiotics, Enzyme Inhibitors, Xray Crystallography.
Researchers (15)
Organisations (2)
Abstract
Infections caused by antibiotic-resistant bacteria continue to challenge health-care systems worldwide. We face growing resistance of Gram-positive and Gram-negative pathogens that cause infections in hospitals and in the community, with the so-called antibiotic-resistant ‘superbugs’ that now represent a major global health problem. It has been reported that 25,000 Europeans die each year as a direct consequence of infections with multidrug resistant strains of pathogenic bacteria, with an estimated economic impact of 1.5 billion Euro per year. However, the pipeline for new drugs is small, because the major pharmaceutical companies have largely abandoned antibiotic discovery even though new drugs are urgently needed. The obstacles of having few new antimicrobials on the horizon and facing increasing frequency of multidrug resistance mean that we must redouble our efforts in the search for new antimicrobials. It is imperative that we continue to search for new antibacterial drugs through innovative screening methods, and undertake rational drug design using the advances provided by protein crystal structures.
Peptidoglycan is a macromolecule that is essential for and specific to the bacterial cell wall. The enzymes involved in its biosynthetic pathway constitute potential targets for the discovery of new antibiotics. During the past 15 years, the group of PI Gobec has developed a number of important peptidoglycan biosynthesis inhibitors, the most important of which are inhibitors of the Mur enzymes (MurA to MurF) and DdlB, and of penicillin-binding proteins. In this Project, we will push forward the development of these inhibitors and optimise their on-target activities, and physico-chemical and pharmacokinetic properties.
Our approach to optimisation of inhibitors will combine the extensive knowledge within our team and our international collaborators of target enzymes and their inhibition, with cutting edge drug discovery and medicinal chemistry techniques. The Project will also benefit from detailed structural analyses, which will enable rapid in-silico design of improved inhibitor scaffolds, and subsequently, identification of novel and potent inhibitors with antibacterial activity. The optimisation of inhibitors is based on an iterative approach including computational design, and synthesis of libraries of inhibitor analogues, followed by biochemical, structural, microbiological, preliminary pharmacokinetic and toxicological evaluation. We expect to develop at least two optimised lead compounds or clinical candidates with potential to be taken forward in collaboration with the pharmaceutical industry, or to form the basis for creation of a Start-up Company. These are very important steps towards development of new broad-action antibacterials that will be of key importance in the fight against bacterial resistance. It is thus the intention of this Project to fill the gap between the burden of infections due to multidrug-resistant bacteria and the decreasing level of new antibiotics in development.
The results of the Project will be published in high-ranking, peer-reviewed journals and be the subject of international patent applications. Involvement of an industrial partner will allow the transfer of knowledge to the Slovenian pharmaceutical industry. Through their research achievements, the Project PI and the team members have demonstrated that the Project is feasible and that all of required equipment is available. The Project will take advantage of our existing network of international collaboration, which was largely created during the FP6 Project EUR-INTAFAR, coordinated at the Faculty of Pharmacy by PI Gobec (collaborations with universities of Paris, Leeds, Liege and Warwick, and Institute of Structural Biology in Grenoble). In addition, the leadership experience of PI Gobec (Vice-Dean, Faculty of Pharmacy, 2005-2007; Dean of Faculty 2007-2011) will assure optimal coordination and running of the Project.
Significance for science
The importance of the proposed research Project for the development of science resides in (i) discovery of novel drugs in an important therapeutic area, and in (ii) development of methods for drug design, synthesis and study of their molecular mechanisms of action. The Project provided an important contribution to the discovery of innovative antibacterial drugs with novel mechanisms of action. Discovery of novel antibacterial drugs is a great challenge to science due to the ever-increasing threat of bacterial resistance to currently used antibacterial drugs. In the last decade, the major pharmaceutical companies have largely abandoned the antibiotic discovery field due to many unresolved scientific problems and to poor financial returns. It is therefore very important that this scientific gap is filled by academic research groups that can devote their full attention to this goal and can perform the pre-clinical steps of antibiotic drug discovery, which can then progress further together with the pharmaceutical industry. Within the Project, important drug discovery tools were used and developed in close collaboration with Slovene and international partners: - Rational design and synthesis of new lead compounds and potential drugs; - Computational methods for structure-based drug design; - De-novo design of new enzyme inhibitors; - Development and optimisation of new synthetic methods (e.g., including, but not limited to, parallel synthesis, microwave-assisted synthesis, use of modern catalysts); - Development of simple and rapid methods for biochemical evaluation of enzyme inhibitors (i.e., drug candidates). Special emphasis was devoted to the application of the above-mentioned tools in the field of antibacterial drug discovery. With the development of small molecule, non-covalent and/or covalent inhibitors of peptidoglycan biosynthesis, and their introduction into clinics, we can overcome the problem of emerging resistance to antibacterials and significantly reduce the number of deaths caused by nosocomial and other infections.
Significance for the country
Research, development and production of antibacterial agents have in the past constituted an important basis for the development of the Slovenian pharmaceutical industry. Discovery of novel innovative drugs and introducing them to the market in cooperation with strategic partners is a way to assure sustained growth for the Slovenian pharmaceutical industry, which is currently one of the major players in the Slovenian economy. The current generic nature of the Slovenian pharmaceutical industry does not preclude its evolution into a research-oriented industry. Knowledge about the discovery of new antibacterial agents relevant for this Project is important also for the generic pharmaceutical industry. The researchers who participated in the proposed research Project will gain competences for autonomous creative work in the pharmaceutical industry, where they will create novel research focuses. This is especially important due to the ongoing globalisation of the Slovenian pharmaceutical industry (such as the merger of Lek d.d. with Novartis). The participating researchers are now also perfectly trained for research work at universities, other research institutes, and governmental agencies. The proposed research programme has generated new, and mastered existing, knowledge, both of which are of paramount importance for sustained development of the pharmaceutical industry and drug-oriented research in Slovenia. Fostering scientific excellence, which is one of the major goals of the proposed research Project, will contribute to the affirmation of Slovenian science through publications in leading scientific journals (like Nature Communications, Journal of Medicinal Chemistry, Plos ONE). This has contributed to the creation and preservation of the country's national identity in Europe and in the world.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
