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

Autoři: Sandra M. Skovdal aff001;  Stig Hill Christiansen aff004;  Karen Singers Johansen aff005;  Ole Viborg aff006;  Niels Henrik Bruun aff007;  Søren Jensen-Fangel aff002;  Ida Elisabeth Holm aff008;  Thomas Vorup-Jensen aff004;  Eskild Petersen aff001
Působiště autorů: Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark aff001;  Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark aff002;  Interdisciplinary Nanoscience Center (iNANO), Faculty of Science and Technology, Aarhus University, Aarhus, Denmark aff003;  Biophysical Immunology Laboratory, Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark aff004;  Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark aff005;  Intensive Care Unit, Department of Anesthesiology, Aarhus University Hospital, Skejby, Denmark aff006;  Biostatistical Advisory Service (BIAS), Department of Public Health, Faculty of Health, Aarhus University, Aarhus, Denmark aff007;  Department of Pathology, Randers Regional Hospital, Randers, Denmark aff008
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223647


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.

Klíčová slova:

Antibiotics – Antimicrobials – Gram negative bacteria – Inflammation – Inhalation – Pig models – Ventilators – Mannitol


1. El Chakhtoura NG, Saade E, Iovleva A, Yasmin M, Wilson B, Perez F, et al. Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy. Expert Rev Anti Infect Ther. 2018;16(2):89–110. doi: 10.1080/14787210.2018.1425139 29310479

2. Chong CR, Sullivan DJ. New uses for old drugs. Nature. 2007 Aug 9;448(7154):645–6. doi: 10.1038/448645a 17687303

3. Bush K. Investigational Agents for the Treatment of Gram-Negative Bacterial Infections: A Reality Check. ACS Infect Dis. 2015 Nov 13;1(11):509–11. doi: 10.1021/acsinfecdis.5b00100 27623407

4. Christiansen SH, Murphy RA, Juul-Madsen K, Fredborg M, Hvam ML, Axelgaard E, et al. The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria. Sci Rep. 2017 Nov 15;7(1):15653. doi: 10.1038/s41598-017-15969-3 29142299

5. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995 Jul;45(7):1268–76. doi: 10.1212/wnl.45.7.1268 7617181

6. Boster AL, Ford CC, Neudorfer O, Gilgun-Sherki Y. Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2015 Jun;15(6):575–86. doi: 10.1586/14737175.2015.1040768 25924547

7. Ziemssen T, Ashtamker N, Rubinchick S, Knappertz V, Comi G. Long-term safety and tolerability of glatiramer acetate 20 mg/ml in the treatment of relapsing forms of multiple sclerosis. Expert Opin Drug Saf. 2017 Feb;16(2):247–55. doi: 10.1080/14740338.2017.1274728 27989217

8. Prod’homme T, Zamvil SS. The Evolving Mechanisms of Action of Glatiramer Acetate. Cold Spring Harb Perspect Med. 2019 Feb 1;9(2).

9. Christiansen SH, Zhang X, Juul-Madsen K, Hvam ML, Vad BS, Behrens MA, et al. The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage. Biochim Biophys Acta Biomembr. 2017;1859(3):425–37. doi: 10.1016/j.bbamem.2017.01.001 28064019

10. Sierra JM, Fusté E, Rabanal F, Vinuesa T, Viñas M. An overview of antimicrobial peptides and the latest advances in their development. Expert Opin Biol Ther. 2017 Jun 3;17(6):663–76. doi: 10.1080/14712598.2017.1315402 28368216

11. Bekendtgørelse af lov om dyreforsøg1) [Internet]. LBK nr 474 May 15, 2014. [cited 2019 May 2]. Available from:

12. European Commission. Legislation for the protection of animals used for scientific purposes—Environment [Internet]. [cited 2019 Feb 28]. Available from:

13. Flume PA, Aitken ML, Bilton D, Agent P, Charlton B, Forster E, et al. Optimising inhaled mannitol for cystic fibrosis in an adult population. Breathe Sheff Engl. 2015 Mar;11(1):39–48.

14. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657–80. 3450848

15. Selmaj K, Barkhof F, Belova AN, Wolf C, van den Tweel ER, Oberyé JJ, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler Houndmills Basingstoke Engl. 2017 Dec;23(14):1909–17.

16. Aharoni R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev. 2013 Mar;12(5):543–53. doi: 10.1016/j.autrev.2012.09.005 23051633

17. Widdicombe JH. Volume of airway surface liquid in health and disease. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1566.

18. Weinstock-Guttman B, Nair KV, Glajch JL, Ganguly TC, Kantor D. Two decades of glatiramer acetate: From initial discovery to the current development of generics. J Neurol Sci. 2017 May 15;376:255–9. doi: 10.1016/j.jns.2017.03.030 28431621

19. Cruz J, Ortiz C, Guzmán F, Fernández-Lafuente R, Torres R. Antimicrobial peptides: promising compounds against pathogenic microorganisms. Curr Med Chem. 2014;21(20):2299–321. doi: 10.2174/0929867321666140217110155 24533812

20. Karaiskos I, Souli M, Galani I, Giamarellou H. Colistin: still a lifesaver for the 21st century? Expert Opin Drug Metab Toxicol. 2017 Jan 2;13(1):59–71. doi: 10.1080/17425255.2017.1230200 27573251

21. Pletzer D, Coleman SR, Hancock RE. Anti-biofilm peptides as a new weapon in antimicrobial warfare. Curr Opin Microbiol. 2016;33:35–40. doi: 10.1016/j.mib.2016.05.016 27318321

22. Pletzer D, Mansour SC, Hancock REW. Synergy between conventional antibiotics and anti-biofilm peptides in a murine, sub-cutaneous abscess model caused by recalcitrant ESKAPE pathogens. PLoS Pathog. 2018;14(6):e1007084. doi: 10.1371/journal.ppat.1007084 29928049

23. Murphy RA, Harrison J, Schelenz S, Davies JC. P125 The multiple sclerosis drug, glatiramer acetate, acts as a resistance breaker with antibiotics from different classes against cystic fibrosis strains of Pseudomonas aeruginosa. J Cyst Fibros. 2019;18;S93.

Článek vyšel v časopise


2019 Číslo 10