Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA

A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.     

Calibration and evaluation of optical systems for full-field strain measurement

The design and testing of a reference material for the calibration of optical systems for strain measurement is described, together with the design and testing of a standardized test material that allows the evaluation and assessment of fitness for purpose of the most sophisticated optical system for strain measurement. A classification system for the steps in the measurement process is also proposed and allows the development of a unified approach to diagnostic testing of components or sub-systems in an optical system for strain measurement based on any optical technique. The results described arise from a European study known as SPOTS whose objectives were to begin to fill the gap caused by a lack of standards.