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Metagenomic and transcriptomic analysis of colistin resistance in gram negative pathogens and adaptation to colistin resistance during progression from tolerome to resistome
Turkey (TurkMSIC) - Koc University , Istanbul
Koc University, Medical Faculty, Department of Microbiology Topkapı, Davutpasa Cd. No. 4, 34010 Zeytinburnu/Istanbul
Prof.Dr.Fusun Can, Student Master Cansel Vatansever
Type of Research Project
- Basic science
What is the background of the project?
New therapeutic approaches are needed for treatment of multidrug-resistant pathogens. Colistin resistance is significant advantage for generations of bacteria, but changes during adaptation to resistance have a cost on the cell and sometimes could cause significant loss of virulence. Bacteria developed strategies for minimizing costs on transcriptional and metabolic pathways. The components of adaptation process should be identified to find target for alternative drugs. Recent studies have focused on in-vitro adaptation of susceptible ancestor of colistin resistant strain. Currently identification of “TOLEROM”, has brought new perspective for solution of this problem. These cells called “lag” phase prolonged cells, are the precursors of persistent cells and resistant bacteria. Therefore, determination of metabolic changes in these cells will allow us early identification of new drug targets.
What is the aim of the project?
To determine new drug targets for elimination of colistin resistance in early stage of tolerant to persister progression by metagenomic and transcriptomic analysis under in-vitro and in-vivo colistin stress.
What techniques and methods are used?
In this study, patients with carbapenem resistant colistin susceptible invasive Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa will be monitored. Nine patients who have colistin resistant infections will be included. Susceptible and resistant isolates will be included in adaptation and tolerance studies. Tolerance induction will be performed on susceptible isolates. Persister and tolerant cells will be separated. MDK (minimal duration of killing) will be determined. In resistome study, susceptible and persister cells will be induced by colistin. Then, whole genome analysis and RNA sequencing will be performed on colistin-susceptible isolates, tolerant cells, persister cells, selected generations during resistance induction, and colistin-resistant strains. Alterations in metabolism and virulence of laboratory-induced colistin resistance, clinical resistance, resistance precursor cells will be determined, and new target regions will be identified by bioinformatics. Tolerome and persister cells will be observed by transmission electron microscope and the morphological changes will be determined. The virulence of the samples will be studied by Caenorhabditis elegans fertility model.
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
What are the tasks expected to be accomplished by the student?
Project includes both different microbiological culturing and molecular analysis techniques. The student will perform antimicrobial susceptibility test on clinical isolates. Induction of colistin tolerome and resistome of gram-negative pathogens will be performed by student. These parts of experiment contain microbiological culturing, flow cytometry techniques, tolerome diffusion test, bacterial minimum duration of killing methods. In molecular analysis, extraction of DNA to determine genotyping and to prepare library preparation for whole genome analysis will be performed by student.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The students will participate in weekly seminars that will be given by some of the professors of our department. If they want, they can also participate in doctorate level classes. They can also be informed about subjects outside of the scope of this project. (Prof.Dr.Fusun Can) Subjects: -Cell cycle -DNA, RNA structure and duplication -Isolation of DNA protocols
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 presentation - 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?
No specific skills required.
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
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- • Fridman; O.; A. Goldberg; I. Ronin; N. Shoresh and N. Q. Balaban. 2014. "Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations." Nature 513(7518): 418-421. DOI: 10.1038/nature13469
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