Bosutinib Stimulates Macrophage Survival, Phagocytosis, and Intracellular Killing of Bacteria

Host-acting compounds are emerging as potential alternatives
to
combating 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-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical
applications on the wound reduce the 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 remodeling. 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, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic
in clinical use, results in an additive effect on bacterial clearance
in vitro and in vivo. These results show that bosutinib stimulates
macrophage clearance of bacterial infections through multiple mechanisms
and could be used to boost the host innate immunity to combat drug-resistant
bacterial infections.