Jenny and Antti Wihuri Foundation has awarded Prasanthi Medarametla, PhD, with a grant of 70 000 euros for postdoctoral research. The research will be conducted at Professor Martin Welch group at the Department of Biochemistry, University of Cambridge, UK. The main goal of the research will be to understand the branchpoint of TCA cycle and glyoxylate shunt which is an important metabolic junction in microbiology and antibacterial drug discovery. Furthermore, the research is the continuation of Medarametla’s PhD research.
The target pathogen of the research is Pseuodomonas aeruginosa, which is an opportunistic Gram-negative bacterium causing urinary tract, pulmonary, circulatory, and skin related infections. P. aeruginosa is also associated with certain chronic infections, especially in patients with long-term respiratory ailments such as COPD or cystic fibrosis, or in patients with immune impairments or type-2 diabetes. The treatment of these infections is difficult due to the resistance of P. aeruginosa to a wide range of existing antibiotics such as beta lactams, aminoglycosides, fluoroquinolones, and carbapenems.
P. aeruginosa was recently designated by the World Health Organization as a “critical priority pathogen” against which new research and drug development efforts are urgently needed. During infection scenarios, this pathogen adopts alternative metabolic pathways rather than traditional pathways tailoring the surrounding environment.
TCA cycle is one of the main energy sources for microbial metabolism. In P. aeruginosa, glyoxylate shunt is the alternative pathway that redirects the carbon flux from the TCA cycle for downstream processes. In this project, the researchers will gain an understanding of structural effects of allosteric regulators on two enzymes (Isocitrate lyase (ICL) and isocitrate dehydrogenase (IDH) of the TCA cycle-glyoxylate shunt branchpoint which is upregulated mainly during infection scenarios. The aim of the project will be achieved using structure driven approaches such as mutagenesis studies (in silico), compound screening and X-ray crystallography. Computational studies associated with the research will be carried out at University of Eastern Finland with Professor Antti Poso and the experimental work will be done in the Welch group.
The research project will lay the groundwork for downstream therapeutic developments targeting this key metabolic node in P. aeruginosa and establish new collaborations between University of Eastern Finland and University of Cambridge. The project will also improve Medarametla’s skillset towards the structural biological and experimental techniques.
For further information, please contact:
Prasanthi Medarametla, https://uefconnect.uef.fi/en/person/prasanthi.medarametla/
