Iron-blocking antibacterial therapy with cationic heme-mimetic gallium porphyrin photosensitizer for combating antibiotic resistance and enhancing photodynamic antibacterial activity

Iron is an essential nutrient for bacterial survival and replication. Interfering with iron metabolism is a potential nondrug-resistant antibacterial strategy. Here we propose an iron-blocking antibacterial therapy (IBAT) based on cationic heme-mimetic gallium porphyrin (Ga-CHP). Cations and heme bionics facilitated the uptake of Ga-CHP by bacteria through heme metabolism and are the primary motifs for its broad-spectrum antibacterial activity. Ga-CHP can rapidly kill gram-positive and gram-negative strains, even multidrug-resistant strains. Notably, unlike antibiotics, it is hard for bacteria to evolve drug resistance in terms of phenotypes and mutations. Furthermore, Ga-CHP is also a superior photosensitizer and its antibacterial capability can be further enhanced via synergistic photodynamic therapy in vitro and in vivo due to heme-assisted catalase inactivation. This work presents an innovative antibacterial strategy for addressing antibiotic resistance crisis and enhancing photodynamic antibacterial activity.