Molecular Investigations into the Catalytic Mechanisms and Inhibition of the Aminoglycoside Antibiotic Resistance

The golden age of antibiotics may be at an end. These compounds found clinical use in the 1940s, and their medical benefits were readily apparent, curing once fatal diseases and increasing life expectancy. However, bacteria have responded successfully to this threat by developing resistance to a multitude of antibiotics, and now, once treatable pathogens are again on the warpath. One of the classes of antibiotics to which resistance has arisen is the aminoglycoside aminocyclitols that specifically target the prokaryotic ribosome. The most clinically relevant form of aminoglycoside resistance is the expression of modifying enzymes, including APH(3')-I1Ia and AAC(6')-APH(2") that catalyze the phosphorylation and/or acetylation of a wide range of aminoglycosides. Application of potent, specific inhibitors to these enzymes can provide a means of overcoming resistance, and a thorough understanding of these enzymes will aid in this endeavor. Towards this end, the molecular mechanisms of catalysis for aminoglycoside phosphorylation and acetylation have been investigated. Enzyme-catalyzed aminoglycoside phosphorylation likely operates through a dissociative-like mechanis