A novel CXCL8(3-72) K11R/G31P-BPI₂₃₃ hybrid protein modulates neutrophil-driven inflammation and protects against carbapenem-resistant Acinetobacter baumannii infection.
9 affiliations
- 1China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College.
- 2National Center for Respiratory Medicine, Beijing, People's Republic of China.
- 3State Key Laboratory of Respiratory Health and Multimorbidity, Beijing, People's Republic of China.
- 4National Clinical Research Center for Respiratory Diseases, Beijing, People's Republic of China.
- 5New Cornerstone Science Laboratory, Beijing, People's Republic of China.
- 6Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
- 7Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China.
- 8Anjun Genetech Co., Ltd, Beijing, People's Republic of China.
- 9Changping Laboratory, Chinese Academy of Medical Sciences & Peking Union Medical College.
Abstract
Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a severe global health threat. Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most critical threats among CRGNB, and effective non-antibiotic therapeutic strategies are urgently needed. Bactericidal/permeability-increasing protein (BPI)-derived molecules display antibacterial and endotoxin-neutralizing activities against Gram-negative bacteria, whereas CXCL8(3-72) K11R/G31P (G31P), an analog of CXCL8 with the mutations of CXCL8 at K11 and G31 positions, could antagonize ELR-CXC chemokine-mediated neutrophil chemotaxis. Here, we engineered a dual-function fusion protein, G31P-BPI₂₃₃, to combine BPI-mediated antibacterial activity with modulation of neutrophil-driven inflammation. Recombinant G31P-BPI₂₃₃ was expressed in CHO-K1 cells and characterized through safety evaluation, endotoxin neutralization, bactericidal, serum killing, neutrophil killing, chemotaxis, cytokine, phagocytosis, and NET-associated marker assays, followed by validation in mouse models of CRAB septicemia and pneumonia. Short-term safety assessment suggested preliminary tolerability over 24 h, while G31P-BPI₂₃₃ reduced residual endotoxin activity and exhibited concentration-dependent bactericidal activity against multiple Gram-negative bacteria. At molar-matched doses, it retained G31P-mediated inhibition of neutrophil migration and BPI₂₃₃-associated bactericidal and cytokine-suppressive activities. In CRAB models, G31P-BPI₂₃₃ improved septicemia survival and reduced pneumonia-associated bacterial burden and inflammatory injury, with endpoint-specific advantages over G31P, BPI₂₃₃, or their equimolar mixture. Several pneumonia outcomes did not differ significantly between G31P-BPI₂₃₃ and colistin. Mechanistic studies using BPI-deficient mice further demonstrated that endogenous BPI contributes to bacterial clearance, endotoxin control, and neutrophil maturation and effector function during CRAB infection. Collectively, these findings identify G31P-BPI₂₃₃ as a promising host-directed antibacterial fusion protein for severe CRAB infection, with potential translational implications for the broader management of CRGNB.
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BibTeX
@article{pu2026novel,
title = {{A novel CXCL8(3-72) K11R/G31P-BPI₂₃₃ hybrid protein modulates neutrophil-driven inflammation and protects against carbapenem-resistant Acinetobacter baumannii infection.}},
author = {Danni Pu and Wei Cao and Jindong Chen and Rongrong Song and Jiankang Zhao and Bin Cao},
journal = {Emerging microbes \& infections},
year = {2026},
month = oct,
doi = {10.1080/22221751.2026.2741787},
url = {https://europepmc.org/article/MED/42876256},
note = {CC BY},
}
RIS
TY - JOUR
TI - A novel CXCL8(3-72) K11R/G31P-BPI₂₃₃ hybrid protein modulates neutrophil-driven inflammation and protects against carbapenem-resistant Acinetobacter baumannii infection.
AU - Danni Pu
AU - Wei Cao
AU - Jindong Chen
AU - Rongrong Song
AU - Jiankang Zhao
AU - Bin Cao
PY - 2026
DA - 2026/10/15
JO - Emerging microbes & infections
DO - 10.1080/22221751.2026.2741787
UR - https://europepmc.org/article/MED/42876256
AB - Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a severe global health threat. Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most critical threats among CRGNB, and effective non-antibiotic therapeutic strategies are urgently needed. Bactericidal/permeability-increasing protein (BPI)-derived molecules display antibacterial and endotoxin-neutralizing activities against Gram-negative bacteria, whereas CXCL8(3-72) K11R/G31P (G31P), an analog of CXCL8 with the mutations of CXCL8 at K11 and G31 positions, could antagonize ELR-CXC chemokine-mediated neutrophil chemotaxis. Here, we engineered a dual-function fusion protein, G31P-BPI₂₃₃, to combine BPI-mediated antibacterial activity with modulation of neutrophil-driven inflammation. Recombinant G31P-BPI₂₃₃ was expressed in CHO-K1 cells and characterized through safety evaluation, endotoxin neutralization, bactericidal, serum killing, neutrophil killing, chemotaxis, cytokine, phagocytosis, and NET-associated marker assays, followed by validation in mouse models of CRAB septicemia and pneumonia. Short-term safety assessment suggested preliminary tolerability over 24 h, while G31P-BPI₂₃₃ reduced residual endotoxin activity and exhibited concentration-dependent bactericidal activity against multiple Gram-negative bacteria. At molar-matched doses, it retained G31P-mediated inhibition of neutrophil migration and BPI₂₃₃-associated bactericidal and cytokine-suppressive activities. In CRAB models, G31P-BPI₂₃₃ improved septicemia survival and reduced pneumonia-associated bacterial burden and inflammatory injury, with endpoint-specific advantages over G31P, BPI₂₃₃, or their equimolar mixture. Several pneumonia outcomes did not differ significantly between G31P-BPI₂₃₃ and colistin. Mechanistic studies using BPI-deficient mice further demonstrated that endogenous BPI contributes to bacterial clearance, endotoxin control, and neutrophil maturation and effector function during CRAB infection. Collectively, these findings identify G31P-BPI₂₃₃ as a promising host-directed antibacterial fusion protein for severe CRAB infection, with potential translational implications for the broader management of CRGNB.
SN - 2222-1751
ER -