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Verapamil increases susceptibility of colistin-resistant Acinetobacter baumannii to colistin
Sichen Liu1, Huijing Zhou1, Jingchun Kong2
1Department 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.
Abstract:
Acinetobacter baumannii, which is predominantly responsible for hospital-acquired infections, presents a tremendous clinical challenge due to its increasing antibiotic resistance to colistin (COL), a last-line antibiotic. As a result, the combination of antimicrobial and non-antimicrobial agents is emerging as a more popular treatment approach against infections caused by COL-resistant A. baumannii. This study administered COL and verapamil (VER), that is an antihypertensive and antiarrhythmic agent. We found that the susceptibility of A. baumannii to COL was restored both in vitro and in vivo. Scanning electron microscope and Crystal violet staining showed inhibition of the VER/COL combination on bacterial biofilm formation. Cytotoxicity assay and haemolysis test were used to confirm in vitro safety evaluation. Further experiments using propidium iodide staining revealed that the VER/COL combination improved the therapeutic efficacy of COL by modifying the permeability of bacterial membranes. As demonstrated by reactive oxygen species experiments, the drug combination caused the accumulation of bacterial reactive oxygen species and their eventual death. Additionally, VER/COL treatment significantly reduced the efflux of Rhodamine 123 (Rh123). For the first time, this study identifies the anti-hypertensive drug VER as a COL potentiator against A. baumannii, providing a potential treatment approach against A. baumannii infections and improving patient outcomes.
Insights
Verapamil (VER) restores colistin (COL) effectiveness against resistant Acinetobacter baumannii. This combination inhibits biofilm formation and enhances COL
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Acinetobacter baumannii is a major cause of hospital-acquired infections.
- Increasing antibiotic resistance to colistin (COL), a last-line drug, poses a significant clinical challenge.
- Combination therapy with antimicrobial and non-antimicrobial agents is a promising strategy.
Purpose of the Study:
- To investigate the potential of verapamil (VER), an antihypertensive agent, as a potentiator for colistin (COL) against COL-resistant A. baumannii.
- To evaluate the efficacy and safety of the VER/COL combination in vitro and in vivo.
Main Methods:
- In vitro and in vivo susceptibility testing of A. baumannii to COL/VER combination.
- Scanning electron microscopy and Crystal violet staining for biofilm inhibition assessment.
- Cytotoxicity assays, haemolysis tests, propidium iodide staining, reactive oxygen species experiments, and Rhodamine 123 efflux assays.
Main Results:
- VER restored A. baumannii susceptibility to COL both in vitro and in vivo.
- The VER/COL combination effectively inhibited bacterial biofilm formation.
- VER/COL enhanced COL's therapeutic efficacy by increasing bacterial membrane permeability and causing reactive oxygen species accumulation.
- VER/COL treatment reduced Rhodamine 123 efflux, indicating decreased drug resistance.
Conclusions:
- Verapamil acts as a colistin potentiator against Acinetobacter baumannii.
- The VER/COL combination offers a potential therapeutic strategy for treating infections caused by multidrug-resistant A. baumannii.
- This approach may improve patient outcomes by overcoming colistin resistance.
