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.

中文翻译：

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博舒替尼刺激巨噬细胞存活、吞噬作用和细胞内细菌杀灭

作用于宿主的化合物正在成为对抗抗生素耐药性的潜在替代品。在这里，我们证明博舒替尼（bosutinib）是 FDA 批准的用于治疗慢性粒细胞白血病的化疗药物，不具有任何抗生素活性，但增强巨噬细胞对细菌感染的反应。在体外，博舒替尼刺激小鼠和人类巨噬细胞更有效地杀死细菌。在小鼠伤口感染耐万古霉素粪肠球菌的情况下，单次腹腔注射博舒替尼或在伤口上多次局部应用，可将细菌负荷减少约 10 倍，并通过巨噬细胞耗竭而消除。从机制上讲，博舒替尼通过上调细菌摄取标记物 Dectin-1 和 CD14 的表面表达并促进肌动蛋白重塑来刺激巨噬细胞吞噬细菌。博舒替尼还通过提高细胞内活性氧的水平来刺激细菌杀灭。此外，bosutinib 可驱动 NF-κB 激活，从而保护受感染的巨噬细胞免于死亡。其他 Src 激酶抑制剂（例如 DMAT 和替巴尼布林）也上调巨噬细胞中细菌摄取标记物的表达并增强细胞内细菌杀灭。最后，与博舒替尼和米托蒽醌（另一种临床使用的化疗药物）联合治疗，可对体外和体内细菌清除产生累加效应。这些结果表明，博舒替尼通过多种机制刺激巨噬细胞清除细菌感染，可用于增强宿主先天免疫力以对抗耐药细菌感染。