Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Identification of Intein Inhibitors as Novel Anti-microbials with Relevance to Tuberculosis

Inteins are naturally occurring protein elements that autocatalytically excise themselves from a non-functional 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 anti-mycobacterial strategy (M. Belfort, US Patent, 5,795,731). 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 anti-cancer 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 anti-mycobacterial. 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. An in vitro inhibitor more potent than cisplatin was identified. Structural and biochemical experiments are ongoing to gain insight into the mechanism of action of these platinum compounds, which will lay the groundwork for potential de novo design of novel anti-microbials.

Seth Pearson 1
Brian Callahan2
Georges Belfort1
Marlene Belfort2

1Howard P. Isermann Department of Chemical and Biological Engineering
The Center for Biotechnology and Interdisciplinary Studies
Rensselaer Polytechnic Institute
Troy, NY 12180
2Department of Biological Sciences
The RNA Institute
University at Albany
Albany, NY 12222

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