The extensive use of antibiotics has exacerbated the emergence of drug-resistant strains in most human pathogens, a global problem with devastating implications for treating infectious diseases and classes of commercially available antibiotics. Over the last 20 years, there has been no development of novel antibiotics targeting bacterial infections. As a result, new antibiotics and novel bacterial targets are urgently needed. The sodium-dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) is a key respiratory enzyme and the primary sodium ion transporter in many pathogenic bacteria, including Vibrio cholerae, the bacterial agent of cholera. Na+-NQR provides energy to the cell of pathogenic bacteria, as well as energizes the membrane, drives nutrient uptake, pH regulation, cell motility, secretion of toxins, and other homeostatic processes. Na+-NQR has been recognized as an optimal drug target due to its critical role in bacterial metabolism, absence in mammalian cells, and unique structural motifs, allowing the discovery of drugs that can act specifically on this enzyme. Several Na+-NQR inhibitors have been reported in the literature such as korormicin and HQNO (2-n-heptyl-4-hydroxyquinoline N-oxide). Unfortunately, these inhibitors are not specific and at high concentrations are toxic to human cells. Our group has identified phenazine compounds as novel inhibitors of Na+-NQR. Herein, we report the synthesis, inhibition, and toxicity against HeLa and HFF cell lines of different phenazine-based derivatives as novel class of antibiotics agent that specifically target and inhibit the Vibrio cholerae Na+- NQR enzyme.

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

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