Palladium(II) complexes suppress biofilm formation and virulence in multidrug-resistant Staphylococcus aureus

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MDRSA) and its ability to form biofilms on host tissues and indwelling devices necessitate the development of alternative therapeutic strategies beyond conventional bactericidal approaches. Two series of palladium(II) metal complexes, derived from α-picolinic acid and substituted anilines, namely QSL_Pd 1A to QSL_Pd 6A and QSL_Pd 1B to QSL_Pd 6B , were tested for their efficacy against multidrug-resistant (MDR) clinical isolates of S.aureus , SA P1966 and SA 2040, and their mechanism of action was elucidated. Among the complexes, QSL_Pd 4A emerged as a potent lead, effectively suppressing biofilm formation with an MBIC₅₀ of 6.26–0.74 µg/mL across both isolates in association with reduced extracellular polymeric substance production and lower cell surface hydrophobicity, without inducing reactive oxygen species. Gene expression analysis revealed downregulation of sarA and icaA, while the agr system remained unaffected. Notably, combinatorial therapy demonstrated a synergistic interaction with commercially available antibiotics, resensitizing the strains. Together, these findings highlight QSL_Pd 4A as a promising antivirulence and antibiofilm agent that attenuates virulence factors, offering a viable strategy to combat MDRSA without exhibiting cytotoxicity.