Domain-domain interactions in the aminoglycoside antibiotic resistance enzyme AAC(6′)-APH(2″)

David D. Boehr, Denis M. Daigle, Gerard D. Wright

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The most common determinant of aminoglycoside antibiotic resistance in Gram positive bacterial pathogens, such as Staphylococcus aureus, is a modifying enzyme, AAC(6′)-APH(2″), capable of acetylating and phosphorylating a wide range of antibiotics. This enzyme is unique in that it is composed of two separable modification domains, and although a number of studies have been conducted on the acetyltransferase and phosphotransferase activities in isolation, little is known about the role and impact of domain interactions on antibiotic resistance. Kinetic analysis and in vivo assessment of a number of N- and C-terminal truncated proteins have demonstrated that the two domains operate independently and do not accentuate one another's resistance activity. However, the two domains are structurally integrated, and mutational analysis has demonstrated that a predicted connecting α-helix is especially critical for maintaining proper structure and function of both activities. AAC(6′)-APH(2″) detoxifies a staggering array of aminoglycosides, where one or both activities make important contributions depending on the antibiotic. Thus, to overcome antibiotic resistance associated with AAC(6′)-APH(2″), aminoglycosides resistant to modification and/or inhibitors against both activities must be employed. Domain-domain interactions in AAC(6′)-APH(2″) offer a unique target for inhibitor strategies, as we show that their disruption simultaneously inhibits both activities > 90%.

Original languageEnglish (US)
Pages (from-to)9846-9855
Number of pages10
JournalBiochemistry
Volume43
Issue number30
DOIs
StatePublished - Aug 3 2004

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Aminoglycosides
Microbial Drug Resistance
Anti-Bacterial Agents
Enzymes
Acetyltransferases
Staphylococcus aureus
Pathogens
Phosphotransferases
6'-aminoglycoside acetyltransferase-2''-aminoglycoside phosphotransferase
Kinetics
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Boehr, David D. ; Daigle, Denis M. ; Wright, Gerard D. / Domain-domain interactions in the aminoglycoside antibiotic resistance enzyme AAC(6′)-APH(2″). In: Biochemistry. 2004 ; Vol. 43, No. 30. pp. 9846-9855.
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Domain-domain interactions in the aminoglycoside antibiotic resistance enzyme AAC(6′)-APH(2″). / Boehr, David D.; Daigle, Denis M.; Wright, Gerard D.

In: Biochemistry, Vol. 43, No. 30, 03.08.2004, p. 9846-9855.

Research output: Contribution to journalArticle

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