Photodynamic inactivation of E. coli with cationic imidazolyl-porphyrin photosensitizers and their synergic combination with antimicrobial cinnamaldehyde

Bacterial infections are a global health concern, particularly due to the increasing resistance of bacteria to antibiotics. Multi-drug resistance (MDR) is a considerable challenge, and novel approaches are needed to treat bacterial infections. Photodynamic inactivation (PDI) of microorganisms is increasingly recognized as an effective method to inactivate a broad spectrum of bacteria and overcome resistance mechanisms. This study presents the synthesis of a new cationic 5,15-di-imidazolyl porphyrin derivative and the impact of n-octanol/water partition coefficient (log P ) values of this class of photosensitizers on PDI efficacy of Escherichia coli . The derivative with log P = –0.5, IP-H-OH 2+ , achieved a remarkable 3 log CFU reduction of E. coli at 100 nM with only 1.36 J/cm 2 light dose at 415 nm, twice as effective as the second-best porphyrin IP-H-Me 2+ , of log P = –1.35. We relate the rapid uptake of IP-H-OH 2+ by E. coli to improved PDI and the very low uptake of a fluorinated derivative, IP-H-CF 3 2+ , log P ≈ 1, to its poor performance. Combination of PDI with cinnamaldehyde, a major component of the cinnamon plant known to alter bacteria cell membranes, offered synergic inactivation of E. coli (7 log CFU reduction), using 50 nM of IP-H-OH 2+ and just 1.36 J/cm 2 light dose. The success of combining PDI with this natural compound broadens the scope of therapies for MDR infections that do not add drug resistance. In vivo studies on a mouse model of wound infection showed the potential of cationic 5,15-di-imidazolyl porphyrins to treat clinically relevant infected wounds. Graphical Abstract