Screening the Ribosome for New Target Sites



 DESCRIPTION (provided by applicant): Nucleic acids are avenues for drug design, both as therapeutics and as targets. Here we propose to establish new methods for identifying antibiotic ribosome targets and lead compounds. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. We are developing fast and low cost methods to screen sequence-specific small molecules for novel anti- ribosomal activities. We will construct sequence-specific ribosomal targeting oligomers as antibacterials, that can be effectively delivered inside the cell. Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that- inactivate the ribosome, stopping bacterial protein synthesis and causing bacterial death. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against anti-bacterial agents. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide delivery, RNA targeted screening and antibacterial studies, describes the development of sequence-specific cell permeable binders of rRNA as antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in antibacterial therapy. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit bacterial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics.