Neutrophil-mediated delivery of the combination of colistin and azithromycin for the treatment of bacterial infection

Jiacong Gao; Xueyan Hu; Congjuan Xu; Mingming Guo; Shouyi Li; Fan Yang; Xiaolei Pan; Fangyu Zhou; Yongxin Jin; Fang Bai; Zhihui Cheng; Zhenzhou Wu; Shuiping Chen; Xinglu Huang; Weihui Wu

doi:10.1016/j.isci.2022.105035

Neutrophil-mediated delivery of the combination of colistin and azithromycin for the treatment of bacterial infection

iScience. 2022 Aug 30;25(9):105035. doi: 10.1016/j.isci.2022.105035. eCollection 2022 Sep 16.

Authors

Jiacong Gao¹, Xueyan Hu^{2

3}, Congjuan Xu¹, Mingming Guo⁴, Shouyi Li¹, Fan Yang¹, Xiaolei Pan¹, Fangyu Zhou¹, Yongxin Jin¹, Fang Bai¹, Zhihui Cheng¹, Zhenzhou Wu⁴, Shuiping Chen⁵, Xinglu Huang^{2

3}, Weihui Wu¹

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
² Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
³ Joint Laboratory of Nanozymes, College of Life Sciences, Nankai University, Tianjin 300071, China.
⁴ College of Life Sciences, Nankai University, Tianjin 300071, China.
⁵ Department of Laboratory Medicine, 5th Medical Center of Chinese PLA General Hospital, Beijing, China.

Abstract

Novel treatment strategies are in urgent need to deal with the rapid development of antibiotic-resistant superbugs. Combination therapies and targeted drug delivery have been exploited to promote treatment efficacies. In this study, we loaded neutrophils with azithromycin and colistin to combine the advantages of antibiotic combinations, targeted delivery, and immunomodulatory effect of azithromycin to treat infections caused by Gram-negative pathogens. Delivery of colistin into neutrophils was mediated by fusogenic liposome, while azithromycin was directly taken up by neutrophils. Neutrophils loaded with the drugs maintained the abilitity to generate reactive oxygen species and migrate. In vitro assays demonstrated enhanced bactericidal activity against multidrug-resistant pathogens and reduced inflammatory cytokine production by the drug-loaded neutrophils. A single intravenous administration of the drug-loaded neutrophils effectively protected mice from Pseudomonas aeruginosa infection in an acute pneumonia model. This study provides a potential effective therapeutic approach for the treatment of bacterial infections.

Keywords: Immunology; bacteriology; microbiology.