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International Journal of Molecular Sciences

International Journal of Molecular Sciences

IF: 5.6
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Restoring Colistin Sensitivity in Multidrug-Resistant Pathogenic E. coli Using Cinacalcet Hydrochloride

Published:28 October 2024 DOI: 10.3390/ijms252111574 PMID: 39519127
Chenchen Wang,?Ziyi Zhang,?Di Liu,?Xiaodan Li,?Zhaoran Zhang,?Yan Zeng,?Wenqi Dong,?Chen Tan,?Manli Liu

Abstract

Restoring colistin's efficacy is crucial in addressing the resistance crisis of colistin. This study utilized a high-throughput screening method to identify 43 compounds from 800 FDA-approved drugs that exhibited significant antibacterial effects when combined with colistin. Among these, cinacalcet hydrochloride (CH) was selected for its potential synergistic effect with colistin against multidrug-resistant (MDR) E. coli strains, including mcr-1-positive strains. A series of experiments revealed that the combination of CH and colistin showed strong synergy, especially in mcr-1-positive strains, restoring colistin sensitivity. The combination significantly inhibited bacterial growth and reduced CFU counts more effectively than either drug alone. Additionally, CH and colistin together significantly inhibited biofilm formation and eradicated existing biofilms, as visualized through confocal microscopy. Mechanistic studies showed that the combination increased bacterial membrane permeability and disrupted membrane integrity. The treatment also elevated extracellular ATP release and ROS production, indicating oxidative stress-induced bacterial death. Safety evaluations showed that the combination did not increase toxicity in host cells. Finally, animal models further validated the combination's efficacy. Overall, this study showed that the combination of colistin and CH significantly restored colistin sensitivity in mcr-1-positive E. coli, revealing their synergistic antibacterial mechanism involving membrane damage and oxidative stress, with promising clinical applications.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Cinacalcet hydrochloride 364782-34-3 C22H23ClF3N 566 suppliers $5.00-$1732.50
Cinacalcet hydrochloride 364782-34-3 C22H23ClF3N 566 suppliers $5.00-$1732.50
Cinacalcet hydrochloride 364782-34-3 C22H23ClF3N 566 suppliers $5.00-$1732.50
Cinacalcet hydrochloride 364782-34-3 C22H23ClF3N 566 suppliers $5.00-$1732.50
Cinacalcet HCl 364782-34-3 - Inquiry
Cinacalcet HCl 364782-34-3 - Inquiry
Cinacalcet Hydrochloride 364782-34-3 - Inquiry
Cinacalcet Hydrochloride 364782-34-3 - Inquiry

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