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

Colistin (COL) is a cationic cyclic peptide that disrupts the membranes of Gram-negative bacteria and is often used as a last resort antibiotic against multidrug-resistant strains. The emergence of plasmid-borne mcr genes, which confer transferable COL resistance, has raised serious concerns, particularly in strains also carrying extended-spectrum β-lactamase and carbapenemase genes. Standard antimicrobial susceptibility testing (AST), performed in enriched bacteriological media, indicates no activity of COL against mcr+ strains, leading to its exclusion from treatment regimens. However, these media poorly reflect in vivo physiology and lack host immune components. Here we show that COL retained bactericidal activity against mcr-1+ Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica when tested in tissue culture medium containing physiological bicarbonate. COL enhanced serum complement deposition on bacterial surfaces and synergized with human serum to kill pathogens. At clinically achievable concentrations, COL killed mcr-1+ strains in freshly isolated human blood and was effective as monotherapy in a murine E. coli bacteremia model. These findings suggest that COL, currently dismissed based on conventional AST, may offer clinical benefit against mcr-1+ infections when evaluated under more physiological conditions - warranting reconsideration in clinical microbiology practices and future trials for high-risk patients.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-04-22
DOI
https://doi.org/10.1172/jci170690
Citations
2
Primary Topic
Probiotics and Fermented Foods
Type
article
Field-Weighted Citation Impact
2.32

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article

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

Elisabet Bjånes, Melanie Chang, George Sakoulas, Angelica M. Riestra et al.
2 citations
Journal of Clinical Investigation
Probiotics and Fermented Foods
2.32
article

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

Elisabet Bjånes, Melanie Chang, George Sakoulas, Angelica M. Riestra, Monika Kumaraswamy, Sang‐Hun Jung, Fatemeh Askarian, Samira Dahesh, Satoshi Uchiyama, Armin Kousha, Victor Nizet, Hideya Seo, Yinzhi Lang, Jonathan M. Monk, Jürgen B. Bulitta, Gunnar Bondsäter, Anabel Flores, Natalie Chavarria, Victoria Nilsson, T.E. Clark
article en
2 citations

Abstract

Colistin (COL) is a cationic cyclic peptide that disrupts the membranes of Gram-negative bacteria and is often used as a last resort antibiotic against multidrug-resistant strains. The emergence of plasmid-borne mcr genes, which confer transferable COL resistance, has raised serious concerns, particularly in strains also carrying extended-spectrum β-lactamase and carbapenemase genes. Standard antimicrobial susceptibility testing (AST), performed in enriched bacteriological media, indicates no activity of COL against mcr+ strains, leading to its exclusion from treatment regimens. However, these media poorly reflect in vivo physiology and lack host immune components. Here we show that COL retained bactericidal activity against mcr-1+ Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica when tested in tissue culture medium containing physiological bicarbonate. COL enhanced serum complement deposition on bacterial surfaces and synergized with human serum to kill pathogens. At clinically achievable concentrations, COL killed mcr-1+ strains in freshly isolated human blood and was effective as monotherapy in a murine E. coli bacteremia model. These findings suggest that COL, currently dismissed based on conventional AST, may offer clinical benefit against mcr-1+ infections when evaluated under more physiological conditions - warranting reconsideration in clinical microbiology practices and future trials for high-risk patients.

Journal of Clinical InvestigationVol. 135(12)
California Baptist University (US), China Medical University (TW), Lund University (SE), The University of Texas at Tyler (US), Kyoto University (JP), San Diego State University (US), University of Florida (US), University of California San Diego (US), Sharp Rees-Stealy Medical Group (US), Q Therapeutics (United States) (US), VA San Diego Healthcare System (US), Office of Infectious Diseases (US), La Jolla Bioengineering Institute (US), University of Montana (US), The University of Texas Health Science Center at Tyler (US), National Yang Ming Chiao Tung University (TW)
National Institutes of Health
Zero hunger
Openalex Percentile: Top 13%
Probiotics and Fermented Foods
2.32
DOIOpen Access PDFOpenAlex
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