Bosutinib stimulates macrophage survival, phagocytosis and intracellular killing of bacteria

Abstract

AbstractHost-acting compounds are emerging as potential alternatives to combat antibiotic resistance. Here, we show that bosutinib, an FDA-approved chemotherapeutic for treating chronic myelogenous leukemia, does not possess any antibiotic activity but enhances macrophage responses to bacterial infection.In vitro, bosutinib stimulates murine and human macrophages to kill bacteria more effectively. In a murine wound infection with vancomycin-resistantEnterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduces bacterial load by approximately 10-fold, which is abolished by macrophage depletion. Mechanistically, bosutinib stimulates macrophage phagocytosis of bacteria by upregulating surface expression of bacterial uptake markers Dectin-1 and CD14 and promoting actin remodelling. Bosutinib also stimulates bacterial killing by elevating the intracellular levels of reactive oxygen species. Moreover, bosutinib drives NF-κB activation which protects infected macrophages from dying. Other Src kinase inhibitors such as DMAT and Tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, co-treatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearancein vitroandin vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infection through multiple mechanisms and could be used to boost host innate immunity to combat drug-resistant bacterial infections.SignificanceThis study shows that bosutinib, an FDA-approved chemotherapeutic, stimulates macrophage responses to antibiotic-resistant bacterial infection by enhancing phagocytosis and intracellular killing of bacteria and promoting survival of infected macrophages. These findings suggest that bosutinib could serve as an adjuvant therapy to combat drug resistant bacterial infections and opens the possibility to target Src kinases to boost innate immunity in general.