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Projects / Programmes source: ARIS

Development of antibacterial compounds targeting validated enzymes in peptidoglycan biosynthesis

Research activity

Code Science Field Subfield
1.09.00  Natural sciences and mathematics  Pharmacy   

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
Drug discovery; Antibacterial agents; Fragment-based drug discovery; Enzyme inhibitors; Covalent inhibitors.
Evaluation (rules)
source: COBISS
Researchers (23)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  24290  PhD Matej Butala  Biochemistry and molecular biology  Researcher  2020 - 2023  237 
2.  53672  Sandra Cetin  Pharmacy  Researcher  2020 - 2021 
3.  50400  PhD Ana Dolšak  Pharmacy  Researcher  2022  27 
4.  26512  PhD Rok Frlan  Pharmacy  Researcher  2020 - 2023  117 
5.  15284  PhD Stanislav Gobec  Pharmacy  Head  2020 - 2023  849 
6.  08329  PhD Simona Golič Grdadolnik  Chemistry  Researcher  2020 - 2023  323 
7.  30378  PhD Majda Golob  Veterinarian medicine  Researcher  2020 - 2023  187 
8.  50814  PhD Katarina Grabrijan  Pharmacy  Junior researcher  2020 - 2022  12 
9.  53283  Maja Hostnik  Biochemistry and molecular biology  Researcher  2022 - 2023  19 
10.  32036  PhD Martina Hrast Rambaher  Pharmacy  Researcher  2020  142 
11.  06734  PhD Dušanka Janežič  Computer intensive methods and applications  Researcher  2020 - 2023  504 
12.  04648  PhD Janko Kos  Biotechnical sciences  Researcher  2020 - 2023  1,166 
13.  33908  PhD Urban Košak  Pharmacy  Researcher  2020 - 2023  59 
14.  55449  Martina Mravinec  Biochemistry and molecular biology  Researcher  2021  11 
15.  50459  Iza Ogris  Chemistry  Junior researcher  2020 - 2023  42 
16.  19170  PhD Urša Pečar Fonović  Pharmacy  Researcher  2020 - 2023  145 
17.  32035  PhD Anja Pišlar  Biotechnology  Researcher  2020 - 2022  171 
18.  52376  PhD Matic Proj  Pharmacy  Junior researcher  2020 - 2023  67 
19.  57309  Tjaša Slokan  Pharmacy  Researcher  2022 - 2023 
20.  52378  Nika Strašek Benedik  Pharmacy  Junior researcher  2020 - 2023  30 
21.  12682  PhD Irena Zdovc  Veterinarian medicine  Researcher  2020 - 2023  470 
22.  56423  Maša Zorman  Pharmacy  Researcher  2021 - 2022  10 
23.  22659  PhD Simon Žakelj  Pharmacy  Researcher  2020 - 2023  162 
Organisations (5)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,412 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,237 
3.  0406  University of Ljubljana, Veterinary Faculty  Ljubljana  1627139  10,934 
4.  0481  University of Ljubljana, Biotechnical Faculty  Ljubljana  1626914  67,219 
5.  2790  University of Primorska, Faculty of mathematics, Natural Sciences and Information Technologies  Koper  1810014009  17,883 
Abstract
Infections caused by antibiotic-resistant bacteria continue to challenge health-care systems worldwide. We face a 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. The obstacles of having only a 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. There is therefore an urgent need that medicinal chemists develop new antibacterial lead compounds and clinical candidates that bind to validated antibacterial drug targets, as this will enable development of novel antimicrobial drugs. Peptidoglycan is a macromolecule that is essential for bacterial survival and unique to the bacterial cell wall. The enzymes involved in its biosynthetic pathway constitute potential targets for the discovery of new antimicrobials. Among the intracellular enzymes of peptidoglycan biosynthesis, only two enzymes are validated antibacterial targets by inhibitors that are in clinical use: MurA is validated by fosfomycin, which is used for the treatment of urinary infections, and DdlB is validated by cycloserine, which is a second line drug for the treatment of tuberculosis. Therefore, these two enzymes will be targeted in the present Project by fragment-based drug discovery (FBDD). FBDD identifies low-molecular-weight ligands (~150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined and is used to facilitate their optimization into potent lead compounds. In addition to classical FBDD approach, where fragments with non-covalent interactions with the target protein are sought, we will also use an innovative approach, where FBDD is used to develop covalent inhibitors. Covalent inhibitors are compounds designed to bind covalently to a specific molecular target and thereby supress its biological function. By careful design, a high degree of selectivity has recently been built into covalent inhibitors, resulting in many clinical candidates and approved drugs. During this Project, we aim to achieve two major objectives: objective 1 is to perform screening of a library of covalent and non-covalent fragments on target enzymes MurA and DdlB, and objective 2 is to perform fragment-to-lead development of selected hit-fragments. First, libraries of fragments will be screened on target enzymes, and then the binding modes of fragments will be determined with X-ray crystallography or NMR. In the next step, structure-based design will be used to generate the ideas how to improve and grow the fragments, and these improved compounds will be synthesized. All target compounds will be pharmacologically evaluated. The work will be iterative and will proceed in a typical drug discovery iterative loop consisting of design, synthesis, biochemical evaluation and structural evaluation, where the latter will be used to start new development iteration. We expect to identify at least five fragment hits on each enzyme (MurA and DdlB) with micromolar inhibitory potency (IC50 or Ki values below 100 µM) and to develop these hits into 1-2 lead compounds active against each target enzyme with sub-micromolar inhibitory potencies (IC50 or Ki values below 1 µM) and good in vitro antibacterial activities (MIC values on most important pathogenic strain below 16 mg/L). The lead compounds developed will have drug-like properties, low or no in vitro cytotoxicity, and good in vitro pharmacokinetics properties. These results will represent significant contribution to the development of new antibacterials that target early stages of peptidoglycan biosynthesis.
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