Intein as a novel anti-microbial strategy
Inteins interrupt three different proteins essential for the viability of Mycobacterium tuberculosis and some of the same proteins found in other bacteria (Table below). Preventing intein splicing, and thus the formation of functional post-processed proteins, suggests that intein inhibition may be used as a novel anti-mycobacterial strategy.
Cisplatin, an FDA approved anti-cancer drug, is a potent inhibitor of intein splicing, both in vitro and in vivo. Due to its high toxicity, however, cisplatin has limited clinical value as an anti-mycobacterial, but can and is being used for structural binding studies with NMR. Several cisplatin analogs were selected for further study using an in vitro fluorescent reporter splicing assay, in an effort to identify compounds that retained potent inhibitory activity while minimizing the toxicity associated with cisplatin. In silico molecular design approaches will be used to search for new inhibitors. We collaborate with Marlene Belfort, UAlbany and Stephen J. Lippard, MIT on this project.