Investigation on the reversal effect of closantel on colistin resistance in MCR-1 positive Escherichia coli based on dose-response relationship

Abstract

Background: The lack of research on the dose-response relationship of adjuvants in reversing colistin resistance will lead to a lack of scientific theoretical basis for determining the dosage of adjuvants in clinical combination therapy plans or their compound formulations.

Objectives: This study investigates the dose-response relationship of the deworming drug closantel (CST) on the reversal of colistin resistance in mcr-1-positive Escherichia coli (E. coli).

Methods: Firstly, the reversal effect of different concentrations of CST on colistin resistance in mcr-1-positive E. coli was analysed using broth microdilution method, checkerboard method and time-killing curves. Then, the inhibitory effect of CST on the development of colistin resistance, as well as the haemolytic and cytotoxic properties of CST, was analysed. Finally, the in vivo efficacy of the combination of CST and colistin was evaluated.

Results: Both the checkerboard assays and the time-killing curves indicate that there is a special dose-response relationship between CST and its reversal effect on colistin resistance, which is not concentration-dependent. High reversal efficiency can be achieved within a low concentration range. However, as the CST concentration increases, the ability to reverse colistin resistance remains unchanged or decreases, which resulted in a gradual decrease in reversal efficiency. Additionally, CST can inhibit the development of colistin resistance and reduce the cytotoxicity of colistin. Importantly, in a mouse model of E. coli infection, the combination of CST and colistin showed a significant therapeutic effect.

Conclusions: This study indicates a special dose-response relationship between CST and its reversal effect on colistin resistance, which was not concentration-dependent.