1. Repurposing cetylpyridinium chloride and domiphen bromide as phosphoethanolamine transferase inhibitor to combat colistin-resistant Enterobacterales.
- Author
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Xu C, Cheng Q, Chen K, Kin So P, Jin W, Gu Y, Wong IL, Chan EWC, Wong KY, Chan KF, and Chen S
- Subjects
- Animals, Female, Mice, Disease Models, Animal, Drug Repositioning, Drug Resistance, Bacterial drug effects, Enterobacteriaceae drug effects, Enterobacteriaceae Infections drug therapy, Enterobacteriaceae Infections microbiology, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Cetylpyridinium pharmacology, Colistin pharmacology, Ethanolaminephosphotransferase metabolism, Ethanolaminephosphotransferase antagonists & inhibitors, Ethanolaminephosphotransferase genetics
- Abstract
The emergence of plasmid-encoded colistin resistance mechanisms, MCR-1, a phosphoethanolamine transferase, rendered colistin ineffective as last resort antibiotic against severe infections caused by clinical Gram-negative bacterial pathogens. Through screening FDA-approved drug library, we identified two structurally similar compounds, namely cetylpyridinium chloride (CET) and domiphen bromide (DOM), which potentiated colistin activity in both colistin-resistant and susceptible Enterobacterales. These compounds were found to insert their long carbon chain to a hydrophobic pocket of bacterial phosphoethanolamine transferases including MCR-1, competitively blocking the binding of lipid A tail for substrate recognition and modification, resulting in the increase of bacterial sensitivity to colistin. In addition, these compounds were also found to dissipate bacterial membrane potential leading to the increase of bacterial sensitivity to colistin. Importantly, combinational use of DOM with colistin exhibited remarkable protection of test animals against infections by colistin-resistant bacteria in both mouse thigh infection and sepsis models. For mice infected by colistin-susceptible bacteria, the combinational use of DOM and colistin enable us to use lower dose of colistin to for efficient treatment. These properties render DOM excellent adjuvant candidates that help transform colistin into a highly potent antimicrobial agent for treatment of colistin-resistant Gram-negative bacterial infections and allowed us to use of a much lower dosage of colistin to reduce its toxicity against colistin-susceptible bacterial infection such as carbapenem-resistant Enterobacterales., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)
- Published
- 2024
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