Sodium-dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) is a key respiratory enzyme and the main sodium pump in many pathogenic bacteria, in particular, <i>Vibrio cholerae</i>, the bacterial agent of cholera. The enzyme functions in driving nutrient uptake, cell motility, pH regulation, among other homeostatic processes. Na+-NQR 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 three compounds identified that act as Na+-NQR inhibitors: Endochine, Atovaquone, and Primaquine. 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 will be on Endochine and Atovaquone derivatives with different substituents at indicated points on the molecule to allow for higher specificity and tighter binding to the active site. The goal of this project is to design and synthesize a new class of antibiotic agents that specifically target the <i>Vibrio cholerae</i> Na+-NQR enzyme.

Design and synthesis of inhibitors of sodium-dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) as novel antibiotic agents

ACS Spring 2022

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