Computational and Experimental Approaches to Combating Antibiotic Resistance
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
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.