Overcoming multidrug- and extensively drug-resistant Salmonella Typhi with natural product-metal synergy: Evidence of DNA polymerase inhibition and cell membrane disruption.

The declining efficacy of azithromycin-the primary oral treatment for typhoid fever in XDR-endemic regions-highlights the urgency against drug-resistant Salmonella Typhi. In response, we developed two ƞ6-arene ruthenium(II) series (9-20 and 37-45) by integrating natural product-based antimicrobial motifs with the DNA-intercalating/ROS-generating features of Ru-scaffolds. Among these, complex 11 and 16 exhibited potent activity against MDR and XDR S. Typhi, with lead complex 16 showing MIC90 as low as 0.06 μg/mL and MBC values significantly superior to azithromycin. Time-kill kinetics showed rapid, concentration-dependent bactericidal effect (≥3-log10 CFU reductions within 8 h), while negligible hemolysis (<2 % at 32 μg/mL) confirmed biocompatibility. Mechanistic studies revealed dual action-membrane disruption and DNA replication inhibition-supported by delayed invA amplification (increased Cq at 1 × /2 × MIC90) and strong binding to DNA polymerase III (docking S-scores: -8.01). Favorable ADMET profiling, including high intestinal absorption (TPSA ∼70 Å2) and no CYP450 inhibition, further highlights the potential of these complexes as new option against untreatable typhoid.