We offer a 4- year PhD Position for a motivated and enthusiastic student at the University of Tartu, Institute of Technology.
Title of the project:
Fighting persistent infections by facilitating bacterial permeability to antibiotics and eradicating persister cells
Supervisors: Professor Tanel Tenson, Niilo Kaldalu and Marta Putrinš
The aim of the project is to find drug combinations that are able to eradicate persister cells.
Antibiotic resistance of pathogenic bacteria is a major healthcare threat. Besides spread of resistance, antimicrobial therapy is undermined by persister cells. Persisters are temporarily dormant bacteria that survive bactericidal treatment in non-proliferating state. After a period of dormancy, persisters switch back to growth phenotype and cause a relapse of the infection.
The mechanisms of persister formation are currently under active research. Decreased antibiotic uptake or increased efflux in individual bacteria may have a role in persistence. The decreased uptake and/or increased efflux of the drug are also widespread and clinically significant mechanisms of antibiotic resistance.
During this project, the PhD candidate will:
1. Screen for the compounds that enhance bactericidal activity of antibiotics and facilitate eradication of persister cells.
- combine a library of approved drug molecules with bactericidal antibiotics and select for compounds that enhance killing by antibiotics.
- screen for the compounds that restore sensitivity of resistant bacterial strains to antibiotics.
- test whether compounds, which restore sensitivity to antibiotics, help to kill persister cells.
- test the efficacy of combinations of antibiotics and potentiating compounds against the intracellular model infections in cell culture.
Screening will be performed in collaboration with Dr. Ana Brochado from the University of Würzburg.
2. Identify the molecular mechanisms that enhance killing of bacteria by antibiotics.
- test structural analogues of the hit compounds from the screen for enhancement of bactericidal activity of antibiotics to profile the structure-activity relationship.
- characterize the effects of the compounds on bacterial transcriptome and proteome to identify putative targets and activity mechanisms of the hit compounds.
- verify the mechanisms using functional tests and bacterial gene deletions and/or mutants.
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