Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs

PLoS One. 2019 Oct 10;14(10):e0223647. doi: 10.1371/journal.pone.0223647. eCollection 2019.

Abstract

The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Bronchi / drug effects
  • Bronchi / microbiology
  • Bronchi / pathology
  • Bronchoconstriction / drug effects
  • Female
  • Glatiramer Acetate / administration & dosage*
  • Glatiramer Acetate / pharmacology*
  • Gram-Negative Bacteria / drug effects*
  • Leukocyte Count
  • Lung / drug effects
  • Lung / microbiology*
  • Lung / pathology*
  • Mannitol / administration & dosage
  • Mannitol / pharmacology
  • Mucous Membrane / drug effects
  • Nebulizers and Vaporizers*
  • Swine

Substances

  • Mannitol
  • Glatiramer Acetate

Associated data

  • figshare/10.6084/m9.figshare.9003164

Grants and funding

This work was supported by a grant from the Health Research Fund of Central Denmark Region (https://www.rm.dk/sundhed/faginfo/forskning/region-midtjyllands-sundhedsvidenskabelige-forskningsfond/) for studies on positively charged, random amino acid co-polymers as antibiotics (TECH-2014-627). TV-J was in receipt of funding from the Danish Multiple Sclerosis Society (https://scleroseforeningen.dk/viden-og-nyt/om-os/about-us) for studies on the pharmaceutical mode of action of GA (R34-A255-B143; R62-A619-B143; R89-A1581-B143; R367-A25613-B143; R431-A29821-B143). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.