Journal of Bacteriology & Parasitology

Trans-translation pathway inhibitors have broad-spectrum antibiotic activity and sterilize M. tuberculosis

International Congress on Bacteriology & Infectious Diseases

November 20-22, 2013 DoubleTree by Hilton Baltimore-BWI Airport, MD, USA

Kenneth C. Keiler

Accepted Abstracts: J Bacteriol Parasitol

Abstract:

In bacteria, ribosomes that have stalled during translation are recognized by a ribonucleoprotein complex consisting of tmRNA and the small protein SmpB. tmRNA-SmpB release the stalled ribosome and target the nascent polypeptide for proteolysis through a pathway known as trans-translation. Genes encoding tmRNA and SmpB have been found in all bacterial genomes, but not in higher eukaryotes. Components of the trans-translation machinery are essential for virulence and viability in many pathogenic bacteria, so this pathway is a potential target for antibiotic development. High-throughput screening using a cell-based assay identified inhibitors of both the ribosome release and proteolysis steps of the trans-translation pathway. These inhibitors have broad-spectrum antibiotic activity, with MIC values in the range of 0.1?3 μg/ml for species including Shigella flexneri, Bacillus anthracis, and Mycobacterium tuberculosis. More detailed investigation of the requirement for trans-translation in M. tuberculosis revealed that the pathway is essential for growth in culture and during macrophage infection. Trans-translation inhibitors efficiently killed both growing M. tuberculosis cells and non-proliferating persister cells, suggesting that these compounds could be useful in the treatment of tuberculosis. Overall, these studies validate the use of trans-translation as a target for development of new antibiotics.

Biography :

Kenneth C. Keiler is an Associate Professor of biochemistry and molecular biology at Penn State University. He earned his Ph.D. in biology from the Massachusetts Institute of Technology. He completed post-doctoral fellowships at the Institut de Genetique et de Biologie Moleculaire et Cellulaire in Illkirch, France, and at Stanford University. He studies bacterial development, looking at regulation of gene expression and localization of RNA and protein in bacteria.