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Bosutinib Stimulates Macrophage Survival, Phagocytosis, and Intracellular Killing of Bacteria. | LitMetric

AI Article Synopsis

  • - Bosutinib, a drug approved for leukemia, enhances macrophage responses to bacterial infections despite not having direct antibiotic activity.
  • - In studies, bosutinib significantly reduced bacterial levels in wound infections resistant to vancomycin, largely by boosting macrophage function.
  • - The drug activates immune processes, including increasing certain surface markers on macrophages and promoting the production of harmful molecules to kill bacteria, indicating its potential to fight drug-resistant infections when combined with other treatments.

Article Abstract

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 , 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091880PMC
http://dx.doi.org/10.1021/acsinfecdis.4c00086DOI Listing

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