Identification of intein inhibitors as novel anti-microbials with relevance to tuberculosis

Inteins are naturally occurring protein elements that autocatalytically excise themselves from a nonfunctional precursor and ligate the flanking protein segments with a peptide bond, resulting in a functional protein. Inteins interrupt three proteins essential for the viability of Mycobacterium tuberculosis. Preventing intein splicing, and thus, the formation of functional post-processed proteins suggests that intein inhibition may be used as a novel antimycobacterial strategy (M. Belfort, US Patent, 5795,731). Due to the growing problem of multiple drug-resistant tuberculosis infections, such alternatives to traditional antibiotic regimens are especially appealing. It has been shown that cisplatin, an FDA approved anticancer drug, is a potent inhibitor of intein splicing, both in vitro and in vivo (Zhang et al., (2011) JBC, 286, 1277). Due to its high toxicity, however, cisplatin has limited clinical value as an antimycobacterial. Several cisplatin analogs were selected for further study using an in vitr...