2. Academic Validation
  3. Immunomodulator AS101 restores colistin susceptibility of clinical colistin-resistant Escherichia coli and Klebsiella pneumoniae in vitro and in vivo

Immunomodulator AS101 restores colistin susceptibility of clinical colistin-resistant Escherichia coli and Klebsiella pneumoniae in vitro and in vivo

  • Int J Antimicrob Agents. 2024 Aug 6;64(4):107285. doi: 10.1016/j.ijantimicag.2024.107285.
Haifeng Liu 1,  Ying Zhang 1,  Zeyong Zhong 2,  Yanchun Gong 1,  Pingting Yu 1,  Yuhan Yang 2,  Yichi Zhang 1,  Tieli Zhou 1,  Lijiang Chen 3
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang, China.
  • 2 School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang, China. Electronic address: wyychenlijiang@163.com.
PMID: 39111708 DOI: 10.1016/j.ijantimicag.2024.107285
Abstract

Objectives: Colistin (COL) was once considered to be the last line of defence against multidrug-resistant bacteria belonging to the family Enterobacteriaceae. Due to the misuse of COL, COL-resistant (COL-R) Enterobacteriaceae have emerged. To address this clinical issue and combat COL resistance, novel approaches are urgently needed.

Methods: In this study, the in vitro and in vivo antimicrobial and antibiofilm effects of the immunomodulator AS101 were investigated in combination with COL against COL-R Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae).

Results: Checkerboard assay, time-kill assay, and scanning electron microscopy confirmed the in vitro antimicrobial phenotype, whereas, crystal violet staining and multidimensional confocal laser scanning microscopy with live/dead staining confirmed the antibiofilm capability of the combination therapy. Moreover, the Galleria mellonella Infection model and the mouse Infection model indicated the high in vivo efficacy of the combination therapy. Additionally, cytotoxicity experiments performed using human kidney-derived HK-2 cells and haemolysis assays performed using human erythrocytes collectively demonstrated safety at effective combination concentrations. Furthermore, quantification of the expression of inflammatory cytokines via enzyme-linked immunosorbent assay confirmed the anti-inflammatory advantage of combination therapy. At the mechanistic level, changes in outer and inner membrane permeability and accumulation of ROS levels, which might be potential mechanisms for synergistic antimicrobial effects.

Conclusions: This study found that AS101 can restore COL susceptibility in clinical COL-R E. coli and K. pneumoniae and also has synergistic antibiofilm and anti-inflammatory capabilities. This study provided a novel strategy to combat clinical infections caused by COL-R E. coli and K. pneumoniae.

Keywords

AS101; Anti-inflammatory; Antibiofilm; Colistin; Enterobacteriaceae.

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