Title

Computational and Experimental Approaches to Combating Antibiotic Resistance

Presenter Information

Adam Farley, Murray State University

Major

Chemistry

List all Project Mentors & Advisor(s)

Dr. James R. Cox

Presentation Format

Event

Abstract/Description

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 aminoglycoside 3'- phoshphotransferases (APH(3')). Studies on a specific enzyme, APH(3')-IIIa, have revealed a pi-stacking interaction between the Tyr-42 residue of the enzyme and the adenine ring of a bound nucleotide. The presence of the pi-stacking interaction has provided a basis for exploiting this important contact for inhibitor design and the testing of various nucleosides that can stack with Tyr-42 and block the nucleotide-binding site of APH(3')-IIIa. Enzyme kinetic studies on various nucleosides and nucleoside-type molecules with APH(3')-IIIa have established which type of aromatic systems can block the active site of the enzyme. Computational methods were also utilized to map and explore the electrostatic environment of APH(3')-IIIa and to rationalize the kinetic studies on a variety of potential inhibitors. Overall, experimental and computational studies have revealed a strict electrostatic requirement for inhibitors that target the nucleotide-binding site of APH(3')-IIIa and enabled the development of a molecular template for inhibitor design strategies. This research is a significant step toward the design of APH type enzyme inhibitors and has implications in combating antibiotic resistance.

Other Affiliations

Science and Mathematics

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Computational and Experimental Approaches to Combating Antibiotic Resistance

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 aminoglycoside 3'- phoshphotransferases (APH(3')). Studies on a specific enzyme, APH(3')-IIIa, have revealed a pi-stacking interaction between the Tyr-42 residue of the enzyme and the adenine ring of a bound nucleotide. The presence of the pi-stacking interaction has provided a basis for exploiting this important contact for inhibitor design and the testing of various nucleosides that can stack with Tyr-42 and block the nucleotide-binding site of APH(3')-IIIa. Enzyme kinetic studies on various nucleosides and nucleoside-type molecules with APH(3')-IIIa have established which type of aromatic systems can block the active site of the enzyme. Computational methods were also utilized to map and explore the electrostatic environment of APH(3')-IIIa and to rationalize the kinetic studies on a variety of potential inhibitors. Overall, experimental and computational studies have revealed a strict electrostatic requirement for inhibitors that target the nucleotide-binding site of APH(3')-IIIa and enabled the development of a molecular template for inhibitor design strategies. This research is a significant step toward the design of APH type enzyme inhibitors and has implications in combating antibiotic resistance.