Efficient killing of intracellular bacteria by cationic heme-mimetic gallium porphyrin in vivo

Macrophage infection has long represented highly lethal chronic diseases that possesses recurrent, resistant and refractory traits, thus the development of non-antibiotic drugs capable of penetrating cell membranes and eradicating resistant bacteria concealed within macrophages is a pressing yet formidable challenge. Here we introduce a method using a cationic heme-mimetic gallium porphyrin (Ga-CHP) to treat intracellular macrophage infections through eradicating Staphylococcus aureus concealed within them by 1.6 mu M of Ga-CHP. Notably, this method does not induce detectable drug resistance and the Ga-CHP micro-pinocytosed into the macrophages in an energy-dependent manner can maintain high level stability in harsh lysosomal environment. In addition, the outstanding cytocompatibility of Ga-CHP ensures effective treatment of pathogens without affecting normal macrophages. More importantly, after tail-vein injection of Ga-CHP on abdominally infected mice, it was found to be effective in reducing the bacterial burden in vivo, superior to vancomycin which represents state of the art intracellular antibacterial agents. Meanwhile, the health status of Ga-CHP-treated mice were significantly improved compared with the control group. This work emphasizes the efficacy of Ga-CHP in eradicating intracellular bacteria concealed within macrophages along with its outstanding cytocompatibility, and provides a promising therapeutic strategy for addressing clinical macrophage infections.