Murray State University

Poster Title

Recognizing the Adenine Ring in Type IIa and IIIa Aminoglycoside AntibioticKinases

Institution

Murray State University

Abstract

The rise in bacterial resistance to antibiotics has reached a crisis level and is considered a public health emergency. Pathogenic bacteria have countered the overuse of antibiotics by expressing a multitude of gene products that render the drugs ineffective. A family of bacterial enzymes that serves as detoxifying agents of aminoglycoside antibiotics has been identified as ATP-dependent aminoglycoside 3'-phosphotransferases (APH(3')). Along with hydrogen-bonding interactions, these enzymes utilize a pi-pi stacking interaction involving an aromatic amino acid to bind the adenine ring of bound nucleotides. Our results derived from steady-state kinetics and quantum-mechanical calculations suggest that these contacts with the adenine ring determine the specificity in the adenine-binding region of these enzymes. Compounds that contain guanine-type ring systems do not block the entry of ATP into the active site of the IIa and IIIa enzymes, while other aromatic systems distinct from the adenine ring are competitive inhibitors of the enzymes with respect to ATP. Overall, the data suggests that there are strict electrostatic requirements for recognition in the adenine-binding region of these kinases and that contacts such as the pi-pi stacking interaction may be exploited to design inhibitors of these antibiotic resistance enzymes. Such inhibitors may serve as potentiators of aminoglycoside action and help regain the clinical effectiveness of these antibiotics.

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Recognizing the Adenine Ring in Type IIa and IIIa Aminoglycoside AntibioticKinases

The rise in bacterial resistance to antibiotics has reached a crisis level and is considered a public health emergency. Pathogenic bacteria have countered the overuse of antibiotics by expressing a multitude of gene products that render the drugs ineffective. A family of bacterial enzymes that serves as detoxifying agents of aminoglycoside antibiotics has been identified as ATP-dependent aminoglycoside 3'-phosphotransferases (APH(3')). Along with hydrogen-bonding interactions, these enzymes utilize a pi-pi stacking interaction involving an aromatic amino acid to bind the adenine ring of bound nucleotides. Our results derived from steady-state kinetics and quantum-mechanical calculations suggest that these contacts with the adenine ring determine the specificity in the adenine-binding region of these enzymes. Compounds that contain guanine-type ring systems do not block the entry of ATP into the active site of the IIa and IIIa enzymes, while other aromatic systems distinct from the adenine ring are competitive inhibitors of the enzymes with respect to ATP. Overall, the data suggests that there are strict electrostatic requirements for recognition in the adenine-binding region of these kinases and that contacts such as the pi-pi stacking interaction may be exploited to design inhibitors of these antibiotic resistance enzymes. Such inhibitors may serve as potentiators of aminoglycoside action and help regain the clinical effectiveness of these antibiotics.