Although antibiotics are widely available and effective, infectious diseases caused by bacteria are responsible for millions of deaths each year. Much of this mortality is due to the increasing rise of antibiotic-resistant bacteria easily spread in hospitals and institutions. The emergence of resistant organisms has created a need for new anti-infectives that are less susceptible to antimicrobial resistance. One of the mechanisms used by bacteria to overcome the effectiveness of antibiotics is mutation of the drug target, commonly the rRNA of the ribosome. The overall goal of this project is to develop new anti-infectives by identifying new ribosomal drug targets and all viable mutations of these targets, and using these targets for drug screening. A high throughput genetic system developed in E. coli can be used for identification of rRNA mutations that do not impair ribosome function.
The specific aims of Phase I are 1) construction of a functional E. coli 16S rRNA mutation library; 2) isolation and sequencing of 5000 mutants; and 3) identification of new drug targets by assaying each mutant for function in vivo. In Phase II, new targets and all viable mutations of these targets will be identified and used to screen for new drug leads. ? ?
