Pantothenate sythetase and malate synthase are not essential for in vitro growth but are essential for persistence of M. tuberculosis in chronically infected mice. Following in silico screening in the lab of affiliate faculty member Dr. Pavel Petukhov, selected compounds are either purchased or synthesized and then screened for activity against the enzymes and cultures of non-replicating bacteria. The malate synthase project is supported by an NIH R21 grant.
Shikimate synthase is an essential enzyme for growth. While several crystal structures exist, the large loop movements during catalysis complicate the selection of an appropriate structure for in silico docking studies. Therefore this small, soluble target is being pursued via NMR. Peak assignments have been made and following the confirmation of a solution structure, fragment and ligand-based screening will commence using NMR to determine the details of binding. This project is being performed in collaboration with the Caffrey and Mesecar labs at UIC.
Fructose 1,6 bisphosphate aldolase is an enzyme in the glycolytic/gluconeogenesis pathway for which the structures of the bacterial and eukaryotic enzymes are different enough to consider as a drug target. We have cloned, expressed and purified the M. tuberculosis enzyme and recently obtained 2 (co)crystal structures with resolution at less than 2 angstroms. This project is being performed in collaboration with the Scott Pegan at the University of Denver, Kamolchanok Rukseree at the National Institute for Biotechnology and Genetic Engineering in Thailand and the Mesecar lab at UIC. A second target in gluconeogenesis, fructose bisphosphatase, is also being pursued.
MptpB is a phosphatase that is essential for the survival of M. tuberculosis within macrophages. We are collaborating with two groups, one at U. Manchester in the UK in which we do the chemistry and in vivo efficacy assessment and the other at the U. Indiana in which we do macrophage and mouse bioassays. The former is supported through a UK governmental funding agency.
