Project title: 

Ketol-acid reductoisomerase: An important antituberculosis drug target

Project duration:

6 weeks

 

Description:

The alarming increase in resistance to current medications to treat human tuberculosis (TB) represents a major threat to global human health. The development of inhibitors of ketol-acid reductiosomerase (KARI) as novel anti-TB agents is very urgent. In bacteria and plants KARI is a central enzyme in the biosynthetic pathway of the branched chain amino acids (i.e. leucine, isoleucine and valine), essential building blocks of virtually all proteins. Importantly, this pathway, including KARI, is not present in animals. Thus, highly specific inhibitors of KARI and are not expected to be toxic to the human host. The activity of this pathway has been proven to be essential to the growth and survival of many bacteria, including Mycobacterium tuberculosis (Mt). Thus, this project will provide new classes of therapeutic drug leads to combat TB, and potentially other bacteria. One of the most effective ways to combat resistance is to develop new drugs that have new modes of action. In respect to resistance, KARI is a particularly interesting target since it has several immutable active site features (i.e. metal and NADPH binding sites) that if blocked should result in powerful inhibition. Thus, these compounds should also have a low propensity to develop site-of-action resistance. Thus, the main hypothesis is that inhibitors of KARI can be developed into new drugs to prevent the growth of TB in infected humans.

Expected outcomes and deliverables:

During this winter project, student will acquire a number of skills related to organic synthesis and purification, mass spec, NMR, and enzyme assay.

Suitable for:

This project is open to applications from students with a background in chemistry and biochemistry (preferably).

Primary Supervisors:

 

Associate Prof Luke Guddat

Associate Prof Ross McGeary

Further info:

For more details, please contact:

Dr Waleed Hussein

Editor-in-Chief, Vaccination Research Open Journal (VROJ)

Chemistry Building (No. 68, room 1119), Cooper Road

School of Chemistry and Molecular Biosciences

The University of Queensland 

St Lucia, QLD 4072, Australia

Mob: 0411882875

E-mail: w.hussein@uq.edu.au