Discovery and characterization of synthetic and natural compounds as inhibitors of shikimate kinase from Mycobacterium tuberculosis by LC-MS

Abstract

With the increasing emergence of drug-resistant tuberculosis (TB) and the complication by HIV co-infection, Mycobacterium tuberculosis (Mtb) remains a challenging target for drug discovery. The shikimate pathway, responsible for the biosynthesis of aromatic compounds in microorganisms and higher plants but absent from mammals, has been suggested as a promising target for the development of antimicrobials and herbicides. Gene disruption studies have demonstrated that the operation of the shikimate pathway is essential for the viability of Mtb, and recent research focusing on the enzymes of the pathway has proposed that small molecules acting as inhibitors of these enzymes could result in a new generation of antibiotics for the treatment of tuberculosis. The work in this dissertation is focused on the applications of mass spectrometry and molecular modeling based approaches for the identification of inhibitors of Mycobacterium tuberculosis shikimate kinase (MtSK), the fifth enzyme of the shikimate pathway.