Design, development and mechanistic insights into the enhanced antibacterial activity of mono and bis-phosphonium fluoresceinate ionic liquids

Abstract Configuring ionic liquids (ILs) to generate synergy or to deliver multiple pharmaceutically active ingredients through a single compound is an emerging area in future medicine where phosphonium ionic liquids (PILs) exhibit potential as antibacterial drugs. Herein, we report the strategic development of two purely ionic mono and bis-PILs based on trihexyltetradecyl phosphonium ([TTP]+) contributing as the cation coupled with monoprotonated fluorescein ([HFl]-) and dianionic fluorescein ([Fl2-]) anions through metathesis reaction. In spite of negligible bactericidal effect of [Fl]2-, the [HFl]- and [Fl2- salts exhibit enhanced and selective bactericidal activity at drastically reduced concentrations. [TTP][HFl] exhibits bactericidal effect at 2 times lower concentration against E. coli and [TTP]2[Fl] at 10 times lower concentrations against S. aureus with respect to the precursor [TTP][Cl]. Docking studies of [TTP][HFl] and [TTP]2[Fl] as well as the precursors with two modelled bacterial cell wall fragments and three RNAs indicate direct correlation between best binding pose and experimentally obtained minimum bactericidal concentrations (MBC). The study suggests the inhibition of peptidoglycan maturation through linkage between phenolate of Fl unit and the D -Ala- D -Ala group of the peptide chain in the cell wall fragment as well as inhibition of RNA/DNA synthesis as probable mechanisms of bacterial cell death. This multistaged cell death mechanism explains the appearance of unexpectedly improved antibacterial activity and selectivity in the mono and bis- phosphonium fluorescein salts. Thus, the results recommend strong potential of the studied PILs to be used as new series of broad spectrum antibacterial agents with reduced risk for development of drug resistant strains.