Aminoglycosides with reduced ototoxicity via miRNA targeting

PROJECT SUMMARYAminoglycosides are one of the cheapest and well-known antibiotics in clinical use for over 70 years, but one of the major limitations in their use is their ototoxicity. We are developing fast and low cost methods to develop aminoglycosides with anti- ribosomal activities and reduced toxicity. In this project, we will identify novel aminoglycoside antibacterials, that show reduced ototoxicity. 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 while reducing toxicity. This work addresses an important health issue, antibiotic ototoxicity, and presents creative steps towards a novel solution to this problem.The work proposed here, a multidisciplinary effort using a miRNA binding and inhibition approach, coupled with antibacterial screening and ototoxicity studies using guinea pig models, describes the development and validation of a rapid way to generate novel aminosugar rRNA binders as non-toxic antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available approaches in antibacterial therapy. We propose using novel aminoglycoside modifications and patented NUBAD assays to identify conjugates that show reduced toxicities, opening possibilities for developing RNA targeted therapeutics with reduced toxicity.PROJECT NARRATIVE The proposed project presents a strategy for developing novel aminoglycoside therapeutics with novel miRNA and rRNA discriminating recognition motifs to reduce drug ototoxicities. Antimicrobial resistance occurs when microorganisms (often infectious bacteria, viruses, and certain parasites) are no longer sensitive to drugs that were previously used to treat them; this is of global concern because it hampers our ability to control infectious disease and increases the costs of health care. In order to combat this world-wide problem, innovative strategies for antibiotic drug design must be implemented. The proposed research describes a strategy for improving the therapeutic index of aminoglycosides by designing novel structures that lower their ototoxicity and evade common resistance pathways.