TOWARDS NEW ANTITUBERCULAR DRUGS

Abstract

Tuberculosis, with million new cases every year, still represents a worldwide health threat. This infectious disease is caused by Mycobacterium tuberculosis and affects primarily the lungs, although it can spread to other organs. The peculiar mycobacterial cell wall makes these bacteria resistant to most of the antibiotics and for this reason the first-line effective drugs now available date back to several decades ago. The recent appearance of drug-resistant strains makes the search for new antitubercular therapies more and more urgent. In the framework of a research network funded by the European Commission, a novel class of antitubercular agents, the benzothiazinones (BTZs), were discovered in 2009, which led to the identification of a new enzyme target that is involved in the biosynthesis of the mycobacterial cell wall. This enzyme is the decaprenylphosphoryl-β-D-ribose 2´epimerase (DprE1) which catalyzes an essential step in the biosynthesis of arabinogalactan, one of the mycobacterial cell components. We carried out a thorough biochemical and structural characterization of DprE1 from M. smegmatis with the aim to investigate BTZ mode of action and provide hints for drug optimization.