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

SUMMARY

Host-acting compounds are emerging as potential alternatives to combating antibiotic resistance. Here, the authors, led by GCIR Prof. Kimberly Kline and Prof. Jianzhu Chen, both members of the Singapore-MIT Alliance for Research and Technology Centre, 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.

Full article: https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00086

WHy is it important?

Widespread antimicrobial resistance is a serious global health problem. Compounds that boost the host immune response are emerging as alternative approaches to treat antibiotic-resistant infections. Macrophages play a key role in defending against bacterial infections by recognising, ingesting and killing bacteria intracellularly. In this study, co-led by GCIR professor Kimberly Kline, bosutinib, originally approved for the treatment of leukaemia, showed no direct antibiotic effect, but enhanced the macrophage response to bacterial infection. The results showed that bosutinib increased the ability of human and mouse macrophages to kill bacteria by several mechanisms, enhancing macrophage phagocytosis, intracellular clearance of bacteria and survival of infected macrophages. In mice with antibiotic-resistant wound infections, bosutinib reduced bacteria levels 10-fold when administered intraperitoneally or applied topically. In conclusion, bosutinib can combat drug-resistant bacteria by boosting the host immune response.

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