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...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/180061 |
| _version_ | 1811693321212395520 |
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| author | da Silva, Ronni A. G. Stocks, Claudia J. Hu, Guangan Kline, Kimberly A. Chen, Jianzhu |
| author2 | Singapore-MIT Alliance for Research and Technology Centre |
| author_facet | Singapore-MIT Alliance for Research and Technology Centre da Silva, Ronni A. G. Stocks, Claudia J. Hu, Guangan Kline, Kimberly A. Chen, Jianzhu |
| author_sort | da Silva, Ronni A. G. |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:49:49Z |
| format | Journal Article |
| id | ntu-10356/180061 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:49:49Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1800612024-09-12T15:30:30Z Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria da Silva, Ronni A. G. Stocks, Claudia J. Hu, Guangan Kline, Kimberly A. Chen, Jianzhu Singapore-MIT Alliance for Research and Technology Centre Singapore Centre for Environmental Life Sciences and Engineering Medicine, Health and Life Sciences Immunomodulation Wound infection 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. Ministry of Education (MOE) National Research Foundation (NRF) Published version The study was supported by the National Research Foundation, Prime Minister’s Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE)program, through core funding of the Singapore-MIT Alliance for Research and Technology (SMART) Antimicrobial Resistance Interdisciplinary Research Group (AMR IRG), and partly by the National Research Foundation and Ministry of Education Singapore under its Research Centre of Excellence Programme and by the Singapore Ministry of Education under its Tier 2 program (MOE2019-T2-2-089) awarded to K.A.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2024-09-11T06:30:36Z 2024-09-11T06:30:36Z 2024 Journal Article da Silva, R. A. G., Stocks, C. J., Hu, G., Kline, K. A. & Chen, J. (2024). Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria. ACS Infectious Diseases, 10(5), 1725-1738. https://dx.doi.org/10.1021/acsinfecdis.4c00086 2373-8227 https://hdl.handle.net/10356/180061 10.1021/acsinfecdis.4c00086 38602352 2-s2.0-85190174721 5 10 1725 1738 en MOE2019-T2-2-089 CREATE ACS Infectious Diseases © 2024 The Authors. Published by American Chemical Society. This article is licensed under CC-BY 4.0. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Immunomodulation Wound infection da Silva, Ronni A. G. Stocks, Claudia J. Hu, Guangan Kline, Kimberly A. Chen, Jianzhu Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title | Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title_full | Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title_fullStr | Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title_full_unstemmed | Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title_short | Bosutinib stimulates macrophage survival, phagocytosis, and intracellular killing of bacteria |
| title_sort | bosutinib stimulates macrophage survival phagocytosis and intracellular killing of bacteria |
| topic | Medicine, Health and Life Sciences Immunomodulation Wound infection |
| url | https://hdl.handle.net/10356/180061 |
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