Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Polymyxin B inhibits pro-inflammatory effects of E. coli outer membrane vesicles whilst increasing immune cell uptake and clearance

Abstract

Polymyxin B (PMB) is a peptide based antibiotic that binds the lipid A moiety of lipopolysaccharide (LPS) with a resultant bactericidal effect. The interaction of PMB with LPS presented on outer membrane vesicles (OMVs) is not fully known, however, a sacrificial role of OMVs in protecting bacterial cells by sequestering PMB has been described. Here we assess the ability of PMB to neutralize the immune-stimulatory properties of OMVs whilst modulating the uptake of OMVs in human immune cells. We show for the first time that PMB increases immune cell uptake of Escherichia coli derived OMVs whilst inhibiting TNF and IL-1β production. Therefore, we present a potential new role for PMB in the neutralization of OMVs via LPS masking and increased immune cell uptake.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Mohapatra SS, Dwibedy SK, Padhy I. Polymyxins, the last-resort antibiotics: mode of action, resistance emergence, and potential solutions. J Biosci. 2021;46:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu X, Chen Y, Yang H, Li J, Yu J, Yu Z, et al. Acute toxicity is a dose-limiting factor for intravenous polymyxin B: a safety and pharmacokinetic study in healthy Chinese subjects. J Infect. 2021;82:207–15.

    Article  CAS  PubMed  Google Scholar 

  3. Zavascki AP, Goldani LZ, Li J, Nation RL. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother. 2007;60:1206–15.

    Article  CAS  PubMed  Google Scholar 

  4. Wang PP, Bao P, Sun GX. The relationship between biofilm and outer membrane vesicles: a novel therapy overview. FEMS Microbiol Lett. 2015;362:1–6.

    Article  CAS  PubMed  Google Scholar 

  5. Svennerholm K, Park KS, Wikström J, Lässer C, Crescitelli R, Shelke GV, et al. Escherichia coli outer membrane vesicles can contribute to sepsis induced cardiac dysfunction. Sci Rep. 2017;7:1–11.

    Article  CAS  Google Scholar 

  6. Marchant P, Carreno A, Vivanco E, Silva A, Nevermann J, Otero C, et al. “One for All”: functional transfer of OMV-mediated polymyxin B resistance from salmonella enterica sv. Typhi ΔtolR and ΔdegS to susceptible bacteria. Front Microbiol. 2021;12:672467.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kim SW, Park SB, Im SP, Lee JS, Jung JW, Gong TW, et al. Outer membrane vesicles from β-lactam-resistant Escherichia coli enable the survival of β-lactam-susceptible E. coli in the presence of β-lactam antibiotics. Sci Rep. 2018;8:5402.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Jan AT. Outer membrane vesicles (OMVs) of gram-negative bacteria: a perspective update. Front Microbiol. 2017;8:1053.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Park J, Kim M, Shin B, Kang M, Yang J, Lee TK, et al. A novel decoy strategy for polymyxin resistance in Acinetobacter baumannii. Elife. 2021;10:e66988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Manning AJ, Kuehn MJ. Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol. 2011;11:258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maluta RP, Logue CM, Casas MRT, Meng T, Guastalli EAL, Rojas TCG, et al. Overlapped sequence types (STs) and serogroups of avian pathogenic (APEC) and human extra-intestinal pathogenic (ExPEC) Escherichia coli isolated in Brazil. PLoS ONE. 2014;9:e105016.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mehat JW, van Vliet AHM, La Ragione RM. The Avian Pathogenic Escherichia coli (APEC) pathotype is comprised of multiple distinct, independent genotypes. Avian Pathol. 2021;50:402–16.

    Article  CAS  PubMed  Google Scholar 

  13. Ronco T, Stegger M, Olsen RH, Sekse C, Nordstoga AB, Pohjanvirta T, et al. Spread of avian pathogenic Escherichia coli ST117 O78: H4 in Nordic broiler production. BMC Genomics. 2017;18:1–8.

    Article  Google Scholar 

  14. Ronco T, Stegger M, Andersen PS, Pedersen K, Li L, Thøfner IC, et al. Draft genome sequences of two avian pathogenic Escherichia coli strains of clinical importance, E44 and E51. Genome Announc. 2016;4:0–1.

    Article  Google Scholar 

  15. O’Donoghue EJ, Sirisaengtaksin N, Browning DF, Bielska E, Hadis M, Fernandez-Trillo F, et al. Lipopolysaccharide structure impacts the entry kinetics of bacterial outer membrane vesicles into host cells. PLoS Pathog. 2017;13:e1006760.

    Article  PubMed  PubMed Central  Google Scholar 

  16. McInerney MP, Roberts KD, Thompson PE, Li J, Nation RL, Velkov T, et al. Quantitation of polymyxin–lipopolysaccharide interactions using an image-based fluorescent probe. J Pharm Sci. 2016;105:1006–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Manioglu S, Modaresi SM, Ritzmann N, Thoma J, Overall SA, Harms A, et al. Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane. Nat Commun. 2022;13:6195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goode A, Yeh V, Bonev BB. Interactions of polymyxin B with lipopolysaccharide-containing membranes. Faraday Discuss. 2021;232:317–29.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kagi T, Naganuma R, Inoue A, Noguchi T, Hamano S, Sekiguchi Y, et al. The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages. J Antibiot. 2022;75:29–39.

    Article  CAS  Google Scholar 

  20. Fathalla AM, Chow SH, Naderer T, Zhou QT, Velkov T, Azad M, et al. Polymyxin-induced cell death of human macrophage-like THP-1 and neutrophil-like HL-60 cells associated with the activation of apoptotic pathways. Antimicrob Agents Chemother. 2020;64:e00013–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shah B, Sullivan CJ, Lonergan NE, Stanley S, Soult MC, Britt LD. Circulating bacterial membrane vesicles cause sepsis in rats. Shock. 2012;37:621–8.

    Article  CAS  PubMed  Google Scholar 

  22. Avedissian SN, Liu J, Rhodes NJ, Lee A, Pais GM, Hauser AR, et al. A review of the clinical pharmacokinetics of polymyxin b. Antibiotics. 2019;8:1–11.

    Article  Google Scholar 

  23. Li X, Liu C, Mao Z, Qi S, Song R, Zhou F. Effectiveness of polymyxin B-immobilized hemoperfusion against sepsis and septic shock: a systematic review and meta-analysis. J Crit Care. 2021;63:187–95.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Danish Council for Independent Research (DFF-1032-00242B).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Bradley Whitehead or Peter Nejsum.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Whitehead, B., Antennuci, F., Boysen, A.T. et al. Polymyxin B inhibits pro-inflammatory effects of E. coli outer membrane vesicles whilst increasing immune cell uptake and clearance. J Antibiot 76, 360–364 (2023). https://doi.org/10.1038/s41429-023-00615-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-023-00615-0

Search

Quick links