Discovery of A Multi-Class Antibiotic Potentiator Against Resistant Klebsiella pneumoniae

The rapid rise of multidrug-resistant (MDR) bacterial infections has severely limited treatment options, particularly for Gram-negative pathogens such as Klebsiella pneumoniae, a leading contributor to pneumonia, bloodstream, urinary tract, and surgical-site infections. One strategy to restore antibiotic efficacy is the use of resistance-mitigating agents (RMAs), compounds that re-sensitize bacteria to existing antibiotics without displaying independent antibacterial activity. Herein, we report the results of a high-throughput screen of a 3,200-compound fragment-based library against an MDR K. pneumoniae isolate in the presence of subinhibitory ciprofloxacin. This screen identified a tetrahydrocarbazole-containing compound, 1, as a ciprofloxacin potentiator. Subsequent structure-activity relationship studies yielded a difluorinated analog, compound 5, which potentiated multiple antibiotic classes in MDR K. pneumoniae, reducing MICs up to [≥]16 fold. Further testing demonstrated synergistic interactions between compound 5 and ciprofloxacin, ceftriaxone, cefoxitin, and tetracycline across four genetically diverse MDR K. pneumoniae strains. These findings suggest that tetrahydrocarbazole-containing compounds constitute a promising new class of RMAs with potential for future development as therapies against MDR K. pneumoniae infections.