The therapeutic properties of antibiotics have been significant in extending the average human life expectancy by combating virulent bacterial infections. Consequently, multidrug-resistant (MDR) microorganisms remain a global crisis and are resistant to conventional antibacterial agents. A novel antibiotic target found exclusively in pathogens is referred to as the NADH:Ubiquinone Oxidoreductase (NQR) which is an essential integral membrane bound enzyme used by the bacterium to maintain overall cellular functionality and has been shown to be present in many bacterial strains such as V. Cholerae and H. influenzae. The enzyme serves as a key protein in the electron transport chain of the bacterial cell and operates as a conserved primary Na+ pump that drives many cellular functions such as bioenergetics and virulence factor formation. The six subunit protein shuttles electrons from an NADH cofactor to a ubiquinone substrate which drives the translocation of Na+ ions across the plasma membrane. A targeted library of ubiquinone-like compounds were tested against the enzyme which resulted in the discovery of the Atovaquone lead molecule which is able to suppress the activity of the enzyme and stimulate bacterial cellular death. Progress in the synthesis and modulation of the ubiquinone-like lead compound will be reported resulting in even more potent and selective inhibitors towards the Na+-NQR enzyme complex.

Design and synthesis of naphthoquinone derivatives used to inhibit the virulent bacterial sodium-dependent NADH: Ubiquinone oxidoreductase (NQR)

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