Mechanisms of Protein Synthesis in Bacteria and Protozoa with structure and function

Bacterial translation machinery has been significantly explored since last century, but studies on eukaryotic protein synthesis are still in infancy and focus is mostly on higher eukaryotes.

Mechanistic studies of translation in bacteria and protozoa, often pathogenic to human / other mammals, are however important for identification and characterization of the suitable drug targets and effective inhibitors.

The aim of the project is to study molecular mechanisms of protein synthesis in model bacteria (Escherichia coli) and protozoa (Giardia intestinalis) with high-resolution cryo-EM structures and state-of-the-art quantitative functional assays with quench flow and stopped-flow based fast kinetics. We will characterize the mechanisms of action of selected aminoglycoside antibiotics on both ribosomes.

Particular interest is to test fluorinated aminoglycosides on aminoglycoside-resistant (A1408G) bacterial ribosomes as well as Giardia ribosomes carrying G in 1408 (equivalent) position.

Combination of antibiotics simultaneously targeting peptidyl transferase center and peptide exit tunnel will also be tested. Translation initiation in Giardia will be studied by reconstituting an in vitro translation system.

Further, we will study Giardia cyst ribosomes to understand the mechanism of silencing translation during transition to dormancy.

Our results will enrich fundamental knowledge of protein synthesis and may aid in developing treatment for bacterial and protozoan infections.