Selection of tmRNA Inhibitors as Antibacterial and Plasmid Elimination Agents
Abstract
The goal of this project is to develop lead compounds for antibiotic development targeted to the tmRNA pathway. These antibiotics are expected to have broad host specificity and will be assayed against pathogens of military interest, including Bacillus anthracis. Specifically, this project aims to: 1) develop screening methods for identification of tmRNA pathway inhibitors; 2) identify and optimize inhibitors from libraries of cyclic peptides; 3) test the bactericidal and plasmid elimination efficacy of lead compounds against B. anthracis and other pathogens; and 4) use high-throughput screening methods to identify small molecule inhibitors of the tmRNA pathway. Methods for identifying inhibitors of the tmRNA pathway have been developed and cyclic peptide inhibitors of 4 different steps in the tmRNA pathway have be selected and optimized. These inhibitors have antibiotic activity against B. anthracis, and are particularly potent when used in combination with the linear antibacterial peptide LL-37. Screening methods were adapted and optimized for high-throughput technology, and, through a collaboration with the Genomics Institute of the Novartis Research Foundation, 52 small molecule inhibitors were identified from a library of over 650,000 compounds. These small molecule inhibitors are potent antibiotics, with MIC values <0.2 mg/l.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2010
- Accession Number
- ADA532720
Entities
People
- Kenneth C Keiler
- Stephen Benkovic
Organizations
- Pennsylvania State University