Design and Synthesis of O-Aryloxycarbonyl Hydroxamate Inhibitors for Serine ß-Lactamases

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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.

    Item Description
    Name(s)
    Author: Malico, Lexie
    Thesis advisor: Pratt, Rex
    Date
    April 15, 2016
    Extent
    102 pages
    Language
    eng
    Genre
    Physical Form
    electronic
    Discipline
    Rights and Use
    In Copyright – Non-Commercial Use Permitted
    Digital Collection
    PID
    ir:64