Mycobacterium tuberculosis is the pathogen that causes tuberculosis (TB). According to estimates of the World Health Organization, one third of the world’s population is infected with TB and the disease causes almost 2 million deaths per year. We are working on the development of novel chemotherapeutics that can be used to treat sensitive strains as well as the increasing problem of multi-drug resistant strains. To identify and characterize compounds that inhibit essential enzymes of M. tuberculosis we use fragment screening, enzyme kinetics, biophysical methods like SPR and ITC and structure-based drug design.
The main drug target in our Lab is the alanine racemase (Alr) of various pathogens. This enzyme is a key enzyme in the cell wall biosynthesis of bacteria and a validated drug target in M. tuberculosis. Alanine racemase catalyzes the racemization of L-alanine to D-alanine, and provides the necessary D-alanine precursor for peptidoglycan synthesis.
Recently, Anthony et al. screened 53,000 compounds in terms of their inhibitory activity against M. tuberculosis Alr and identified 7 novel compounds that inhibit alanine racemase with an IC50 in the low microM range (Anthony et al 2011, PLoS one). Efforts are currently underway in our laboratory to study these lead compounds and further characterize the mechanism of action.
Links to a few of our alanine racemase structures:
1XFC The 1.9 A crystal structure of alanine racemase from Mycobacterium tuberculosis.
3HA1 Alanine racemase from Bacillus anthracis (Ames).
4A3Q The 2.15 Angstrom resolution crystal structure of Staphylococcus aureus alanine racemase.
3S46 The crystal structure of alanine racemase from Streptococcus pneumoniae.