Design and Synthesis of New Aminoglycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation

Abstract

The structure and activity of the pseudodisaccharide core found in aminoglycoside antibiotics was probed with a series of synthetic analogues in which the position of amino groups was varied around the glucopyranose ring. The naturally occurring structure neamine was the best in the series according to assays for in vitro RNA binding and antibiotic activity. With this result in hand, neamine was used as a common core structure for the synthesis of new antibiotics, which were evaluated for binding to models of the Escherichia coli 16S A-site ribosomal RNA, in vitro protein synthesis inhibition, and antibiotic activity. Analysis of RNA binding revealed some correlation between the relative affinity and specificity of RNA binding and antibacterial efficacy. However, the correlation was not linear. This result led us to develop the in vitro translation assay in an effort to better understand aminoglycoside−RNA interactions. A linear correlation between in vitro translation inhibition and antibiotic activity w...