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 reduced 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 toxcity 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. The guinea model will also be used to evaluate nephrotoxicity and systemic toxicity. Antibacterial efficacy of the optimized compounds will be 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.
Aminoglycoside antibiotics (AGAs) are potent antibiotics which have long been used as potent broad spectrum antibiotics, with targets including gram-negative pathogens, MRSA, MDR-TB, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Significant limitations of the AGAs, however, are AGA-induced permanent hearing loss (ototoxicity) and nephrotoxicity which are reported to affect up to 20% of the patient population, and susceptibility to resistance due AGA and target modifying enzymes. On the basis of recent advances in the understanding of the molecular basis for AGA-induced ototoxicity, and existing knowledge of the mechanisms of resistance, this proposal seeks to design, and synthesize novel AGAs that do not suffer from the complications of toxicity, are not subject to common mechanisms of resistance, and to evaluate them both in vitro and in animal models for efficacy against gram-positive an gram-negative organisms, and lack of ototoxicity and nephrotoxicity.
