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Novel strategies to overcome antibiotic resistance in Mycobacterium tuberculosis: development of multi-target inhibitors of aminoacyl-tRNA-synthetases
Ukraine (UMSA) - Bogomolets National Medical University
Department of Protein Synthesis Enzymology
Prof. Tukalo Michael, PhD, Dr.Sci
Rybak Mariia, MSc
Required: English Accepted: Ukrainian,Russian
Type of Research Project
- Basic science
What is the background of the project?
Mycobacterium tuberculosis infection remains a major cause of global mortality and morbidity. The rapid development of M. tuberculosis multidrug resistance provides the stimulus for the search of antibiotics with novel mechanisms of action. In the last decade multi-target drugs have attracted much attention for the treatment of diseases associated with drug-resistance. Aminoacyl-tRNA synthetases are promising molecular targets for antibiotic drug design. These enzymes play an indispensable role in protein synthesis catalyzing the synthesis of aminoacyl-tRNAs in the reaction of esterification of specific amino acid to cognate tRNA. Recent experimental results demonstrated that leucyl-tRNA synthetase (LeuRS) is a validated drug target for antituberculosis agents. A number of studies clearly showed that methionyl-tRNA synthetase (MetRS) is a validated molecular target for antibiotic design against Trypanosoma brucei, Leishmania donovani, Plasmodium falciparum, Giardia intestinalis, Staphylococcus aureus, Clostridium difficile etc. Therefore, we selected LeuRS and MetRS M. tuberculosis for development of dual-targeted inhibitors since these enzymes represent promising molecular targets and belong to one subclass of aaRSs and have some similarities in catalytic centers.
What is the aim of the project?
To design and find novel antituberculosis small-molecules compounds with dual- or multi-target activity against aminoacyl-tRNA-synthetases from M. tuberculosis to investigate antibacterial activity of hit compounds toward pathogenic strain H37Rv.
What techniques and methods are used?
Stage 1. Ligand-based virtual screening (programs DOCK та AutoDock). Stage 2. Biochemical screening of compounds (in vitro colorimetric or radiolabeled assays). Stage 3. Optimization of hit compounds. Stage 4. Investigation of compounds antibacterial activity toward pathogenic strain M. tuberculosis H37Rv (National Institute of Allergy and Infectious Diseases (NIAID), USA). Stage 5. Investigation of compounds selectivity against human synthetases (in vitro colorimetric or radiolabeled assays). Stage 6. Crystallization of the most active inhibitors with recombinant enzymes (X-ray scattering).
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
- The student will mainly observe
What are the tasks expected to be accomplished by the student?
1. Student will study how to plan and perform experiments (especially biochemical testing of inhibitors, protein purification etc). 2. Learn modern chromatography techniques for enzymes purification, principles of inhibitors selection. 3. Understand the main rules in development of new assays for inhibitors screening. 4. Perform all experiments under tutor’s supervision. 5. Present all obtained data during the lab meeting or personal discussion with tutors.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Department seminars (1 time per week)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic knowledge in biochemistry and molecular biology
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- 1. Francklyn; C. S.; & Mullen; P. (2019). Progress and Challenges in Aminoacyl-tRNA Synthetase-based Therapeutics. Journal of Biological Chemistry; jbc-REV118.
- 2. Gudzera; O. I.; Golub; A. G.; Bdzhola; V. G.; Volynets; G. P.; Lukashov; S. S.; Kovalenko; O. P.; ... & Tukalo; M. A. (2016). Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase. Bioorganic & medicinal chemistry; 24(5); 1023-1031.
- 3. Gudzera; O.I.; Golub; A.G.; Bdzhola; V.G.; Volynets; G.P.; Kovalenko; O.P.; Boyarshin; K.S.; Yaremchuk; A.D.; Protopopov; M.V.; Yarmoluk; S.M. and Tukalo; M.A. (2016) Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1; 2; 4] triazin-3-one. Journal of enzyme inhibition and medicinal chemistry; 31; 201-207.
- 4. Palencia; A.; Li; X.; Bu; W.; Choi; W.; Ding; C.Z.; Easom; E.E.; Feng; L.; Hernandez; V.; Houston; P. and Liu; L. (2016) Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase. Antimicrobial Agents and Chemotherapy; 60; 6271-6280.
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