Aminoglycoside antibiotics were some of the first natural products identified in the late 1930's to have potent antibacterial activity. Aminoglycosides are a large class of natural product antibiotics (and semi-synthetic derivatives of these compounds) which are used clinically in the treatment of a wide variety of human Gram-positive and Gram-negative bacterial infections. There is still some dispute about their individual targets and mode of action, however, they act as a class on the bacterial ribosome and inhibit protein translation. Resistance to these compounds was apparent soon after their clinical introduction, and a manifold of resistance mechanisms have been identified, including rRNA modifications and ribosomal protein mutations, and a number of different aminoglycoside modifying enzymes. These include enzymes capable of phosphorylating, adenylating and acetylating the amino and hydroxyl groups of the antibiotic. During the fellowship period, the applicant will be involved in identifying resistance genes from clinical isolates of Gram-negative and Gram-positive aminoglycoside resistant strains, attempting to correlate the incidence of resistance genes with the exposure to various aminoglycosides, and express one or more of the genes to identify the substrate selectivity for various aminoglycoside antibiotics.
