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

Abstract

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.