An Evaluation of Alternative Treatment Strategies in Mitigating Colistin Resistance: Targeting Plasmid Transfer Through the Use of Bambermycin or the Protein Coded by the Mcr-1 Gene With Antibodies and Streptomycin.

BACKGROUND

Plasmid mediated antimicrobial resistance continues to be a source of global concern, especially given the limited pipeline of novel antibiotics. The horizontal transfer of the plasmid mediated colistin resistance gene (mcr-1) between microorganisms confer resistance to previously susceptible bacterial strains and renders colistin and polymyxin B antimicrobials ineffective.

OBJECTIVE

To mitigate plasmid mediated colistin resistance using bambermycin and streptomycin on mcr-1 positive field strains of Escherichia coli. Furthermore, to assess if a commercial MCR-1 polyclonal antibody would have any synergistic effect on colistin in killing mcr-1 gene associated colistin-resistant E. coli in vitro.

METHODS

Colistin-resistant E. coli strains recovered from clinical cases were subjected to checkerboard assays and conjugation assays using varying drug combinations viz colistin, bambermycin, streptomycin, MCR-1 antibody and human complement serum, to mitigate drug resistance.

RESULTS

Following conjugation assay, the plasmid bound resistance gene was successfully transferred to J53 E. coli strain with colistin minimum inhibitory concentration (MIC) rising from ≤0.125 to >2 µg/mL conferring resistance to the former organism. The combination of bambermycin and colistin in a checkerboard assay proved to be synergistic in killing mcr-1 associated colistin-resistant strains. The combination of streptomycin, colistin and MCR-1 polyclonal antibody showed additive lethal effect on mcr-1 associated colistin-resistant strains. Bambermycin did not interfere with the transfer of mcr-1 bound plasmid from donors to recipient organism.

CONCLUSION

Further studies on bambermycin's mechanism of action are required, as both inhibiting and enhancing effects have been documented. Similarly, the addition of MCR-1 polyclonal antibody in a checkerboard assay did not enhance colistin's lethal effect on mcr-1 carrying E. coli strains, thus highlighting the need for further research.