Publication Date

April 2016


Rex Pratt




English (United States)


ß-Lactam antibiotics are commonly used in clinical practice to treat bacterial infections. Increasing bacterial resistance to ß-lactam antibiotics is primarily attributed to the production of hydrolytic enzymes termed ß-lactamases. Therefore, the development of novel ß-lactamase inhibitors is critical. Recent investigations by Dr. Ronak Tilvawala in this laboratory into O- (phenoxycarbonyl)-N-[4-amino-4-carboxyl-1-butyl)oxycarbonyl]hydroxylamine (L2) revealed that the compound inhibits the class C serine ß-lactamase of Enterobacter cloacae P99 by forming a hydroxamate acyl-enzyme complex, most likely stabilized by the Tyr 150, Ser 212, and Arg 204 residues in the O-loop of the active site. In the present research, several novel O- aryloxycarbonyl hydroxamate derivatives were designed and synthesized as potential P99 inhibitors in order to elucidate the importance of both the polar and nonpolar groups on the hydroxamic acid side chain of the inhibitor. Kinetic analysis indicated that O-(phenoxycarbonyl)- N-(1-butyloxycarbonyl)hydroxylamine (1), O-(phenoxycarbonyl)-N-[(2-benzyl-1-ethyl) oxycarbonyl]hydroxylamine (2), O-(phenoxycarbonyl)-N-[4-carboxyl-1-butyl)oxycarbonyl] hydroxylamine (3), and O-(phenoxycarbonyl)-N-[4-amino-1-butyl)oxycarbonyl]hydroxylamine (4) were irreversible inhibitors of P99 ß-lactamase. It is likely that 1 inhibits through the same mechanism as O-phenoxycarbonyl-N-(benzy)loxycarbonyl)hydroxylamine (L1), while 2, 3, and 4 inhibit through the same mechanism as L2. Thus suggesting that both the polar and nonpolar side groups play a role in the mechanism of the inhibitor.



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