Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Colistin (COL) is a last-resort antibiotic for multidrug-resistant Gram-negative bacterial infections.
• The spread of plasmid-borne colistin resistance (mcr) genes threatens COL efficacy.
• Standard antimicrobial susceptibility testing (AST) media do not reflect in vivo conditions.

Purpose of the Study:

• To evaluate COL activity against mcr+ Gram-negative bacteria in a physiologically relevant context.
• To investigate COL's interaction with host immune factors like serum complement.
• To assess COL's therapeutic potential in preclinical models of infection.

Main Methods:

• Testing COL against mcr+ Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica in tissue culture media with bicarbonate.
• Assessing COL's effect on serum complement deposition and synergy with human serum.
• Evaluating COL efficacy in a murine model of E. coli bacteremia and in human blood.

Main Results:

• COL demonstrated bactericidal activity against mcr+ strains in bicarbonate-containing media.
• COL promoted complement deposition and synergized with human serum for enhanced bacterial killing.
• COL was effective in human blood and a murine bacteremia model at achievable concentrations.

Conclusions:

• Standard AST may underestimate COL's activity against mcr+ strains.
• COL may be a viable therapeutic option for mcr+ Gram-negative infections when evaluated in a physiologic context.
• Further clinical investigation is warranted for high-risk patients with limited treatment options.