Shaping Next Generation Aminoglycoside Antibiotics for Treatment of Multidrug-Resistant Diseases

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Aminoglycoside antibiotics (AGAs) are potent antibiotics which have long been used as potent broad spectrum antibiotics, with targets including gram negative and gram‐negative pathogens, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Significant limitations of the AGAs, however, are AGA‐induced permanent hearing loss (ototoxicity), which is reported to affect up to 20% of the patient population, nephrotoxicity, and resistance due to AGA and target modifying mechanisms. Based on extensive preliminary results two series of compounds, paromomycin and apramycin derivatives, will be synthesized and optimized for their ability to inhibit Gram positive and Gram negative wild type and multidrug resistant bacteria, and to do so with a much improved toxicity profile. To achieve these ends all synthetic compounds will screened for their ability to inhibit bacterial and eukaryotic ribosomes, indicative of antibacterial activity and toxicity respectively, and for their activity against engineered bacterial strains carrying specific resistance determinants. The results of these assays will be used in a feedback loop to inform the design and synthesis of the next iteration of compounds. A select set of optimized compounds will be screened for ototoxicity in the mouse cochlear explant model and then in the guinea pig model of ototoxicity. Nephrotoxicity will be assayed in three relevant cell lines and for advanced compounds in mice. Antibacterial efficacy of the optimized compounds will be determined in mice. Pharmacokinetics of advanced compounds will determined in mice. At the end of the study, the goal is to have a small validated set of advanced compounds that display broad and potent antibiotic activity against wild type and multidrug resistant Gram positive and Gram negative bacteria, with much reduced toxicity, suitable for further development.