Although many drug-resistant nontyphoidal Salmonella (NTS) infections are reported globally, their treatment is challenging owing to the ineffectiveness of the currently available antimicrobial drugs against resistant bacteria. It is therefore essential to discover novel antimicrobial drugs for the management of these infections. In this study, we report high inhibitory activities of the novel fluoroquinolones (FQs; WQ-3810 and WQ-3334) with substitutions at positions R-1 by 6-amino-3,5-difluoropyridine-2-yl and R-8 by methyl group or bromine, respectively, against wild-type and mutant DNA gyrases of Salmonella Typhimurium. The inhibitory activities of these FQs were assessed against seven amino acid substitutions in DNA gyrases conferring FQ resistance to S. Typhimurium, including high-level resistant mutants, Ser83Ile and Ser83Phe-Asp87Asn by in vitro DNA supercoiling assay. Drug concentrations of WQ compounds with 6-amino-3,5-difluoropyridine-2-yl that suppressed DNA supercoiling by 50% (IC ₅₀ ) were found to be ∼150-fold lower than ciprofloxacin against DNA gyrase with double amino acid substitutions. Our findings highlight the importance of the chemical structure of an FQ drug on its antimicrobial activity. Particularly, the presence of 6-amino-3,5-difluoropyridine-2-yl at R-1 and either methyl group or bromine at R-8 of WQ-3810 and WQ-3334, respectively, was associated with improved antimicrobial activity. Therefore, WQ-3810 and WQ-3334 are promising candidates for use in the treatment of patients infected by FQ-resistant Salmonella spp.

Background/Objectives: Mycobacterium avium, a member of Mycobacterium avium complex (MAC), is an emerging opportunistic pathogen causing MAC-pulmonary disease (PD). Fluoroquinolones (FQs), along with ethambutol (EMB) and rifampicin, are recommended for macrolide-resistant MAC-PD; however, FQ-resistant M. avium have been reported worldwide. WQ-3810 is an FQ with high potency against FQ-resistant pathogens; however, its activity against M. avium has not yet been studied. Methods: In this study, we conducted a DNA supercoiling inhibitory assay to evaluate the inhibitory effect of WQ-3810 on recombinant wild-type (WT) and four mutant DNA gyrases of M. avium and compared the IC₅₀s of WQ-3810 with those of ciprofloxacin (CIP), levofloxacin (LVX), and moxifloxacin (MXF). In addition, we examined WQ-3810’s antimicrobial activity against 11 M. avium clinical isolates, including FQ-resistant isolates, with that of other FQs. Furthermore, we assessed the synergistic action of WQ-3810 with the combination of either EMB or isoniazid (INH). Results: In a DNA supercoiling inhibitory assay, WQ-3810 showed 1.8 to 13.7-fold higher efficacy than LVX and CIP. In the MIC assay, WQ-3810 showed 4 to 8-fold, 2 to 16-fold, and 2 to 4-fold higher antimicrobial activity against FQ-resistant isolates than CIP, LVX, and MXF, respectively. The combination of WQ-3810 and INH exhibited a synergistic relationship. Conclusions: The overall characteristics of WQ-3810 demonstrated greater effectiveness than three other FQs, suggesting that it is a promising option for treating FQ-resistant M. avium infections.