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|Title:||CHARACTERIZATION OF AAC(6')-APH(2"), A BIFUNCTIONAL AMINOGLYCOSIDE MODIFYING ENZYME|
|Authors:||DAIGLE, DENIS M.|
|Advisor:||Wright, Gerard D.|
|Abstract:||<p>AAC(6')-APH(2") is a bifunctional enzyme which catalyzes the inactivation of aminoglycoside antibiotics by ATP-dependant O-phosphorylation and acetyl coenzyme A-dependant N- and O-acetylation. it is the most prominent aminoglycoside-modifying enzyme found in gentamicin-resistant clinical isolates of Enterococci and Staphylococci. Although capable of inactivating all 2-deoxystreptamine aminoglycosides, gentamicin is the most clinically important substrate commonly administered in combination therapies to treat nosocomial Enterococcal infections. Gentamicin-resistant clinical isolates carrying aac(6')-aph(2") are characterized by high level resistance to gentamicins and other aminoglycosides. In an attempt to obtain a more thorough understanding of it's functionalities and develop strategies to inhibit its' function in vivo, studies were initiated to characterize the substrate specificities, the regiospecificities of inactivation, and the potential for generation of lead compounds with inhibitory action towards AAC(6')-APH(2"). The studies reported herein, identify: i) two novel activities exhibited by AAC(6')-APH(2") (a Serine protein kinase activity exhibited by the phosphoransferase APH(2")-Ia and an O-acetyltransfer activity exhibited by the acetyltransferase AAC(6')-Ie, ii) the substrate structural requirements for enzyme/substrate interactions, iii) an unanticipated regiospecificity of inactivation of the 4, 5-disubstituted aminoglycosides and iv) inhibition of the APH(2")-Ia by isoquinolinesulfonamide protein kinase inhibitors.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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