Structural studies on antibiotic-resistance mechanisms and their application to drug design

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Aminoglycosides are broad spectrum antibiotics acting against a variety of Gram-negative and certain Gram-positive bacteria. Aminoglycosides specifically bind to one of the active sites of the bacterial ribosome called the A site, and disturb the fidelity of the decoding process in protein synthesis. Bacteria acquire high-level resistance against aminoglycosides by mutating the position 1408 of the ribosomal RNA A site, from A to G or 1-methyl-A. In the present study, we have performed X-ray analyses of the ribosomal RNA A sites with these antibiotic-resistant mutations and revealed structural bases for the antibiotic resistance conferred by the point mutatations. In addition, we have successfully designed and synthesized a new compound with high activity against antibiotic-resistant bacteria and parasitic protozoa.