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ResearchIn-Press PreviewInfectious diseaseMicrobiology Open Access | 10.1172/JCI170690

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

Monika Kumaraswamy,1 Angelica Riestra,2 Anabel Flores,3 Samira Dahesh,3 Fatemeh Askarian,3 Satoshi Uchiyama,3 Jonathan Monk,4 Sean Jung,5 Gunnar Bondsäter,3 Victoria Nilsson,3 Melanie Chang,3 Jürgen B Bulitta,6 Yinzhi Lang,6 Armin Kousha,3 Elisabet Bjånes,3 Natalie Chavarria,3 Ty'Tianna Clark,2 Hideya Seo,3 George Sakoulas,3 and Victor Nizet3

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Uchiyama, S. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

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1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Chang, M. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Bulitta, J. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Lang, Y. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Kousha, A. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Bjånes, E. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Chavarria, N. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Clark, T. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Seo, H. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Sakoulas, G. in: PubMed | Google Scholar

1Division of Infectious Diseases, UT Tyler, Tyler, United States of America

2Department of Biology, San Diego State University, San Diego, United States of America

3Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, United States of America

4Department of Bioengineering, UCSD, La Jolla, United States of America

5Division of Infectious Diseases and Global Public Health, UCSD, La Jolla, United States of America

6Department of Pharmacotherapy and Translational Research, The University of Florida, Gainesville, United States of America

7Division of Host-Microbe Systems and Therapeutics, UCSD, La Jolla, Japan

Find articles by Nizet, V. in: PubMed | Google Scholar |

Published April 22, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI170690.
Copyright © 2025, Kumaraswamy et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 22, 2025 - Version history
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Abstract

Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged Gram-negative bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against mcr+ strains based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with mcr+ infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we observed that COL exhibits bactericidal activities against mcr+ isolates of Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica in tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the mcr-1+ Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed mcr-1+ E. coli, K. pneumoniae, and S. enterica in freshly isolated human blood and proved effective as monotherapy in a murine model of E. coli bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with mcr-1+ Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high-risk patients with limited therapeutic options.

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graphical abstract
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View Details of genes and mutations implicated in colistin resistance were searched for using the CARD v5.2.1.

View ABRITAMR screens for 196 genes and mutations implicated in colistin resistance.

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Version history
  • Version 1 (April 22, 2025): In-Press Preview
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