Computational investigations of the catalytic mechanism of Staphylococcus aureus transglycosylase: design and chemical synthesis of novel mechanism-based inhibitors.

Bacterial resistance against current medications is a growing problem that will pose significant health problems in the near future. Penicillins are a class of antibiotics that exert there effect by blocking the biosynthesis of the bacterial cell wall by means of inhibition of the transpeptidase protein, an enzyme responsible for the synthesis of the essential glycan chains in the cell wall. An alternative approach to inhibit the growth of the bacterial cell wall would be by inhibition of the transglycosylase enzyme, a protein involved in the polymerisation of the sugar chains that make up the backbone of these glycan chains. Currently there are no medications on the market or in clinical trials that have a mechanism of action of glycosyltransferase inhibition, but it has been shown that blocking the normal function of this enzyme leads to inhibition of bacterial cell growth. The main objective of the current project is to identify potent inhibitors against this transglycosylase enzyme using large-scale molecular dynamics simulations to study the catalytic mechanism of action and kinetics in large detail. Results of these simulations will be used to propose novel chemical compounds that will be synthesized through a collaboration with the University of Leuven. Biochemical testing of the antibacterial effects of these compounds will be performed at the University of Liège.

Keywords:MOLECULAR DYNAMICS, CHEMINFORMATICS, ORGANIC SYNTHESIS, COMPUTER AIDED MOLECULAR MODELLING

Disciplines:Organic chemical synthesis, Bioinformatics and computational biology not elsewhere classified, Infectious diseases