With the rising epidemic of tuberculosis (TB) in developing countries and the increase in resistant TB strains appearing world-wide, there is an urgent need to discover and develop new anti-TB drugs. An innovative approach of using bioengineered bacteria (E. coli) as sources of novel molecules has succeeded in the identification of a series of compounds exhibiting anti-TB activities in our cellular assays. Structure elucidation of one of these active series has shown it to possess a flat heterocyclic core of low molecular weight and solubility. Our goal is to advance this series to the drug development level by 1) identifying a chemical synthetic approach to these isolates amenable for access to gram quantities, 2) utilize our biological testing panel of anti-TB assays to identify the most promising and selective lead compound, 3) optimize the bioactivity, safety, and stability of this lead via further chemical modification of the molecule.
One third of the world's population is infected with the bacteria Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), with approximately 1/2 million cases of drug-resistant TB of which 6.6% of these being extensively drug resistant (X- DR TB). The present drug therapies which originated over 50 years ago can no longer be expected to limit this epidemic. Using a genetically engineered E.coli bacteria to oxidatively metabolize simple chemical starting materials, we have isolated a novel series of anti-TB agents. This series will be modified via organic chemistry leading to the development of a novel, orally active anti-TB drug.
| Klein, Larry L; Petukhova, Valentina; Wan, Baojie et al. (2014) A novel indigoid anti-tuberculosis agent. Bioorg Med Chem Lett 24:268-70 |
| Klein, Larry L; Tufano, Michael D (2013) Synthesis of Substituted Isatins. Tetrahedron Lett 54:1008-1011 |
