Quinolone inhibitors targeting Vibrio cholerae sodium-dependent NADH: Ubiquinone oxidoreductase (NQR)

Antimicrobial agents have been at the forefront of global efforts to treat bacterial infections. However, their efficacy and reliability have steadily declined due to the widespread emergence of multidrug resistance (MDR). This challenge is particularly critical for Vibrio cholerae , the etiological agent of cholera, a disease that remains a significant global health burden in endemic and outbreak-prone regions. The increasing prevalence of MDR V. cholerae strains, coupled with a stagnating pipeline of new antibiotics, underscores the urgent need for novel antibacterial targets and therapeutic strategies. The sodium-translocating NADH:ubiquinone oxidoreductase (NQR) is a ubiquitous and essential aerobic respiratory enzyme found in several MDR bacterial pathogens, including V. cholerae , Pseudomonas aeruginosa , Chlamydia trachomatis , and Klebsiella pneumoniae . Herein, we report the first systematic investigation of quinolone-based inhibitors targeting NQR, involving the design, synthesis, and biological assessment of a series of 3-substituted quinolones inspired by the antimalarial lead compound endochin and other highly toxic quinolones. Our structure-guided optimization strategy mitigates the high toxicity historically associated with quinolone derivatives, yielding analogs with improved safety profiles. These compounds exhibit enhanced potency and selectivity against NQR, highlighting their potential as a new class of antibacterial agents against MDR pathogens. • New quinolone analogs inhibit the sodium-translocating NADH: ubiquinone oxidoreductase (NQR) • which is an essential aerobic respiratory enzyme in MDR bacteria including Vibrio cholerae • The 3-diaryl ether derivative 3r has 58% inhib. at 50 μM and no HeLa toxicity. • Molecular docking in the ubiquinone binding site of NQR informs the SAR.