Nucleobase aminosugars with reduced ototoxicity

PROJECT SUMMARYAminoglycosides are one of the cheapest and well known antibiotics in clinical use for overyearsbut one of the major limitations in their use is their ototoxicityWe are developing fast and low cost methods to develop aminoglycosides with antiribosomal activities and reduced toxicityIn this projectwe will identify novel aminoglycoside antibacterialsthat show reduced ototoxicityComplexes between ribosomal components will be exploited as targets for small molecule drug libraries thatinactivate the ribosomestopping bacterial protein synthesis and causing bacterial death while reducing toxicityThis work addresses an important health issueantibiotic ototoxicityand presents creative steps towards a novel solution to this problemThe work proposed herea multidisciplinary effort encompassing antibacterial screening and ototoxicity studies using zebrafish and guinea pig modelsdescribes the development of novel aminosugar rRNA binders as non toxic antibacterial therapeuticsThe success of the proposed work would be a significant addition to currently available approaches in antibacterial therapyWe propose using novel aminoglycoside modifications and patented NUBAD assays to identify conjugates that show reduced toxicitiesopening possibilities for developing RNA targeted therapeutics with reduced toxicity PROJECT NARRATIVE The proposed project presents a strategy for developing novel aminoglycoside therapeutics with new heterocyclic rRNA recognition motifs to reduce ototoxicitiesAntimicrobial resistance occurs when microorganismsoften infectious bacteriavirusesand certain parasitesare no longer sensitive to drugs that were previously used to treat themthis is of global concern because it hampers our ability to control infectious disease and increases the costs of health careIn order to combat this world wide probleminnovative strategies for antibiotic drug design must be implementedThe 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!