| Abstract
| - Aminoglycoside 3‘-phosphotransferases [APH(3‘)s] phosphorylate aminoglycoside antibiotics, areaction that inactivates the antibiotics. These enzymes are the primary cause of resistance toaminoglycosides in bacteria. APH(3‘)-Ia operates by a random-equilibrium BiBi mechanism, whereasAPH(3‘)-IIIa catalyzes its reaction by the Theorell−Chance mechanism, a form of ordered BiBimechanism. Hence, both substrates have to be present in the active site prior to the transfer ofphosphate by both mechanisms. Four bisubstrate analogues, compounds 1−4, were designed andsynthesized as inhibitors for APH(3‘)s. These compounds are made of adenosine linked covalentlyto the 3‘-hydroxyl of neamine (an aminoglycoside) via all-methylene tethers of 5−8 carbons. The Kivalues measured for these compounds indicated that affinities of APH(3‘)-Ia and APH(3‘)-IIa forcompounds 2 and 3 (six- and seven-carbon tethers, respectively) were the best, and the inhibitionconstants for the two were comparable.
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