Research

Discovery of new inhibitors of bacterial peptidoglycan biosynthesis enzymes MurA and MurB

Code:

Z1-8158

Range:

01. May 2017 - 30. April 2019

Range:

0,33 FTE

Leader:

Marko Jukič

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Nowadays, we are in a transition era where it is evident that therapy of bacterial infections is not a trivial task, understood by modern medicine and supplied with abundant medicines. Emergence of bacterial resistance, globalisation and access to modern medicinal practice together with a decreasing output of antibacterial discovery pipeline, projects a major concern for the future. In the light of multidrug-resistant bacteria, bacteria resistant to the last line of defence drugs and resulting decrease in the efficacy of antibiotics, future research programmes in antibacterial drug design demand ultimate respect and financial engagement from industrial and scientific communities. This postdoctoral scientific project will contribute to the antibacterial drug research by exploring MurA transferase and MurB reductase enzymes as therapeutic targets in antibacterial drug discovery. Both enzymes are present at the intracellular steps in the biosynthesis of UDP-N-acetylmuramyl-pentapeptide – a key building block for the peptidoglycan biosynthesis and bacterial cell-wall construction and are essential for bacterial cell viability. Studied enzymes do not have mammalian homologues and are regarded as one of the prominent targets in antibacterial drug research, sadly with limited scientific data available. Project will use rational and computer-assisted drug design methodologies of ligand-based, structure-based and fragment-based drug design with bioinformatics to identify novel inhibitors of MurA and MurB enzymes. Design phase of the compounds will also be supported by extensive molecular dynamics studies. As the project emphasis will be on the antibacterial drug design, in house in vitro antibacterial testing will be emphasized from the early stages of design all along the project timeframe with supporting toxicological testing. Special attention will be also given to pharmacokinetic properties with CACO and PAMPA permeability testing, all in order to obtain compounds with potential for further in-depth pharmacological evaluation and further development. As no clear mode-of-action is reported for new reported inhibitors of Mur enzymes with antibacterial activity, this project will try to gain an insight in mode-of-action by focusing on collection of commercial compounds with development and organic synthesis of MurA and MurB inhibitors suitable for such studies. As the task is highly interdisciplinary in nature, research will be performed in collaboration with international research network of partners. Ultimate goal of the project is development of MurA and MurB inhibitors with antibacterial activity and an insight into the mode-of-action where inhibition of studied enzyme can be linked to the antibacterial activity.