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Updated: Jun 29, 2025
Antimicrobial Synergy Testing by the Inkjet Printer-assisted Automated Checkerboard Array and the Manual Time-kill Method
Published on: April 18, 2019
The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative
Jie Li1,2,3, Ning Han1,2,3, Yangyang Li1,2,3
1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Background:
The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue.
Methods:
Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models.
Results:
In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models.
Conclusion:
These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
Insights
Oxethazine enhances colistin
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antibiotic resistance, particularly plasmid-mediated, is a significant global health threat.
- Novel strategies are needed to combat multidrug-resistant bacteria.
- Adjuvants that potentiate existing antibiotics offer a promising approach.
Purpose of the Study:
- To investigate the synergistic activity of oxethazine and colistin against resistant bacteria.
- To elucidate the mechanisms underlying this synergistic interaction.
- To evaluate the in vivo efficacy of the combination therapy.
Main Methods:
- In vitro checkerboard assays and time-kill curves were used to assess synergy.
- Mechanistic studies included fluorescent dye, scanning electron microscopy (SEM), and LC-MS/MS.
- In vivo efficacy was tested in Galleria mellonella and mouse sepsis models.
Main Results:
- Oxethazine significantly enhanced colistin's activity against mcr-positive and mcr-negative pathogens.
- The combination disrupted bacterial outer and cytoplasmic membranes, increasing permeability.
- Synergistic treatment led to reactive oxygen species accumulation and bacterial cell death.
- Therapeutic efficacy was improved in both animal models.
Conclusions:
- Oxethazine acts as an effective antibiotic adjuvant for colistin.
- This combination presents a potential strategy for treating infections caused by multidrug-resistant bacteria.
- Further research into oxethazine as an adjuvant is warranted.
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