Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes

Four photosensitizers PS1a-PS4a consisting in multicationic Ruthenium(II) Phthalocyanines (RuPcs) have been evaluated in photodynamic inactivation (PDI) of multiresistant microorganisms. The RuPcs, bearing from 4 to 12 terminal ammonium salts, have been designed to target the microorganisms cytoplasmic cell membrane and display high singlet oxygen quantum yields. In addition, PS3a and PS4a were conceived to exhibit multi-target localization by endowing them with amphiphilic character, using two different structural approaches. Under low light regimes, the two hydrophilic PS1a and PS2a, as well as the amphiphilic PS3a show much stronger response against gram-positive MRSA than that observed for the typical phthalocyanines designed for PDI, namely zinc(II) and palladium(II) complexes, as well as free-base Pcs. Besides, PS1a, PS2a and PS3a show remarkably high activity against the gram-negative E. coli, although weak fungicidal character against fluconazole-resistant C. albicans. Contrasting, the structurally different, amphiphilic PS4a shows only slight activity for Gram-positive bacteria, despite its ability to cross cell membrane and reach internal organelles. Still, PS4a shows a positive synergistic effect against MRSA when combined with doxycycline, exhibiting an increased activity from about 1.5 to about 4.9 log reduction under the light dose of 30 J/cm² and the 0.125 mg/L subinhibitory dose of doxycycline.