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

TY - JOUR

T1 - The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria

AU - Christiansen, Stig Hill

AU - Murphy, Ronan A.

AU - Juul-Madsen, Kristian

AU - Fredborg, Marlene

AU - Hvam, Michael Lykke

AU - Axelgaard, Esben

AU - Skovdal, Sandra M.

AU - Meyer, Rikke Louise

AU - Sorensen, Uffe B. Skov

AU - Moeller, Arne

AU - Nyengaard, Jens Randel

AU - Norskov-Lauritsen, Niels

AU - Wang, Mikala

AU - Gadjeva, Mihaela

AU - Howard, Kenneth A.

AU - Davies, Jane C.

AU - Petersen, Eskild

AU - Vorup-Jensen, Thomas

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - ATOMIC-FORCE MICROSCOPY

KW - MULTIPLE-SCLEROSIS

KW - STAPHYLOCOCCUS-AUREUS

KW - PEPTIDES

KW - TARGET

KW - ANTIBIOTICS

KW - RESISTANCE

KW - CELLS

KW - INFECTIONS

KW - MOLECULES

UR - http://www.scopus.com/inward/record.url?scp=85034417799&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-15969-3

DO - 10.1038/s41598-017-15969-3

M3 - Journal article

C2 - 29142299

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 15653

ER -