Major
Chemistry
Anticipated Graduation Year
2022
Access Type
Restricted Access
Abstract
Sodium dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) is a key respiratory enzyme and the main sodium pump in many pathogenic bacteria, including Vibrio cholerae, the bacterial agent of cholera. This enzyme functions in driving nutrient uptake, cell motility, pH regulation, among other homeostatic processes. The Na+-NQR enzyme has been identified as a promising drug target because it provides energy to bacterial cells and is unique to bacteria. Because of its absence in mammalian cells, inhibition will not create mechanism-based toxic effects in mammals. There have been several compounds identified that act as Na+-NQR inhibitors including clofazimine. When these inhibitors bind with Na+-NQR, enzymatic activity ceases, and highly reactive oxygen species (ROS) are produced, which are lethal to bacteria. The main focus of synthesis in this report will be on clofazimine derivatives with different substituents at indicated points on the molecule to allow for higher specificity, tighter binding to the active site, and higher potency and efficacy. The goal of this project is to design and synthesize a new class of antibiotic agents that specifically target and inhibit the Vibrio cholerae Na+-NQR enzyme.
Faculty Mentors & Instructors
Sebastian Flieger, PhD Candidate, Loyola University Chicago Department of Chemistry and Biochemistry; Daniel P. Becker, PhD, Loyola University Chicago Department of Chemistry and Biochemistry
Supported By
Ming Yuan, Illinois Institute of Technology Department of Biological Sciences; Karino Tuz, Illinois Institute of Technology Department of Biological Sciences; Oscar Juarez, PhD, Illinois Institute of Technology Department of Biological Sciences
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Design and Synthesis of Inhibitors of Sodium Dependent NADH: Ubiquinone Oxidoreductase (Na+-NQR) as New Antibiotic Agents
Sodium dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) is a key respiratory enzyme and the main sodium pump in many pathogenic bacteria, including Vibrio cholerae, the bacterial agent of cholera. This enzyme functions in driving nutrient uptake, cell motility, pH regulation, among other homeostatic processes. The Na+-NQR enzyme has been identified as a promising drug target because it provides energy to bacterial cells and is unique to bacteria. Because of its absence in mammalian cells, inhibition will not create mechanism-based toxic effects in mammals. There have been several compounds identified that act as Na+-NQR inhibitors including clofazimine. When these inhibitors bind with Na+-NQR, enzymatic activity ceases, and highly reactive oxygen species (ROS) are produced, which are lethal to bacteria. The main focus of synthesis in this report will be on clofazimine derivatives with different substituents at indicated points on the molecule to allow for higher specificity, tighter binding to the active site, and higher potency and efficacy. The goal of this project is to design and synthesize a new class of antibiotic agents that specifically target and inhibit the Vibrio cholerae Na+-NQR enzyme.