Evaluation of Streptamine Analogs to Overcome Resistance to Apramycin

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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-positive pathogens, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Apramycin is a novel aminoglycoside antibiotic that retains all of the typical advantages of the aminoglycosides but, because of its unusual structure, offers the additional benefits of avoidance of the vast majority of aminoglycoside resistance determinants and of reduced oto- and nephrotoxicity. As such apramycin is currently in clinical trials in Europe and in the USA for the treatment of multidrug-resistant Gram-negative infections. A major advantage of apramycin is its lack of susceptibility to activity-damaging alteration by aminoglycoside modifying enzymes, with the single exception of the aminoacetyltransferase isozyme AAC(3)-IV, which portends well for its use against carbapenem- resistant Gram-negative infections. Nevertheless, resistance due to the acquisition of the AAC(3)-IV gene will eventually inevitably emerge. The goal of this proposal is to test the novel hypothesis that advanced apramycin analogs (apralogs) can be designed and easily prepared that circumvent the AAC(3)-IV resistance determinant through the introduction of a simple hydroxy or alkoxy group at the 2-position on the deoxystreptamine core of apramycin, ie, based on the streptamine core. To test this novel hypothesis a series of some forty advanced apralogs will be prepared based on the streptamine core and screened, in an iterative feedback loop, for antibacterial activity in the presence of AAC(3)-IV and other resistance mechanisms. Compounds will also be screened for activity at the target level using cell-free translation assays with bacterial ribosomes and for selectivity over eukaryotic ribosomes using comparable cell-free translation assays with mutant bacterial ribosomes carrying human decoding A sites. These later studies will provide a measure of selectivity and are predictive of toxicity, thereby ensuring that the excellent toxicity profile of the parent apramycin is retained in the new analogs. At the end of the study, the goal is to have a small set of advanced compounds that are not susceptible to the AAC(3)-IV mechanism of resistance, and retain the otherwise excellent broad spectrum activity and minimal toxicity of the parent apramycin.