Principal Investigator (PI)
florida international university
The Foundation is providing £45,563 in support.
Neelam Keshwani
GSK would contribute the chemical library for HTS screening. GSK is to provide available nearest neighbors and any information on the identified hits if possible. Medicinal chemistry support or disclosure of synthetic routes to the original hits from GSK is needed first for the resynthesis of the selected hits, and subsequently for SAR to improve the potency and selectivity of validated hits in collaboration with TB Alliance.
Topoisomerase poison inhibitors are highly effective for initiating cell death in anti-bacterial and anti-cancer therapy. These inhibitors lead to the accumulation of the covalent intermediate formed between topoisomerases and cleaved DNA. Every organism must have at least one type IA topoisomerases to resolve topological barriers encountered in DNA replication, recombination, repair that require cleavage and rejoining of a single DNA strand. The type IA topoisomerase in M. tuberculosis, Mtb topoisomerase I (MtbTopI), has been shown in genetic studies to be essential for survival. This enzyme has been characterized biochemically and represents a novel target for development of drugs to be used in new combination therapy for treatment of XDR and MDR TB. A fluorescent assay suitable for HTS has been developed for identification of small molecules that can act as poison inhibitors against MtbTopI. The proposed project would utilize this HTS assay to identify compounds from the GSK corporate chemical library at the Open Lab facilities, including the anti-tubercular subset. In our preliminary screen in collaboration with TB Alliance several hits active against TB have been identified and they have been used in the hit expansion exercise. The identified hit compounds will be confirmed for activity as poison inhibitors of MtbTopI in secondary biochemical and cell based assays. An active compound targeting MtbTopI as mode of action for anti-TB activity will be used as starting point for development of a potent and non-toxic compound for new TB therapy in collaboration with TB Alliance and medicinal chemists at GSK.