The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria

Abstract

Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram-negative bacteria.

Structural Immunology of Complement Receptors 3 and 4

“…However, GA is a complex drug, as demonstrated by the recent observations that it may directly kill T lymphocytes in process similar to LL-37, which is likewise known to possess immunomodulatory properties ( 157 ). The cytotoxicity toward prokaryotes only expands the possible therapeutic influences in MS ( 158 ). However, with the significant role of CR3-expressing macrophages and microglial cells in the pathogenesis of MS, the role of GA as a CR3 antagonist should not be overlooked as part of the PMA.…”

The intestinal microbiota composition in patients with multiple sclerosis receiving different disease-modifying therapies DMT

“…Это позволяет предположить, что разные иммуномодулирующие препараты могут иметь свои бактерии-мишени. В частности, показано [29], что ГА in vitro проявляет антимикробное действие по отношению к грамотрицательным бактериям E. coli и Pseudomonas aeruginosa.…”

Drugs Repurposing for Multi-Drug Resistant Bacterial Infections

“…More specifically, meloxicam has been reported to inhibit biofilm formation of P. aeruginosa by decreasing the extracellular Psl, Pel and alginate production, three vital biofilm exopolysaccharides in this pathogen [26,27]. Moreover, glatiramer acetate, a drug used in the treatment of multiple sclerosis, has also been shown to disrupt biofilm formation by GNB [42]. Finally, azathioprine, an immunosuppressive drug used for the treatment of Crohn's disease and other autoimmune diseases, has exhibited anti-biofilm activity against P. aeruginosa and E. coli through the inhibition of WspR [43].…”