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Antimicrobial Agents and Chemotherapy, May 2006, p. 1835-1840, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1835-1840.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Antibiofilm Activity of GlmU Enzyme Inhibitors against Catheter-Associated Uropathogens

Euan Burton,1 Purushottam V. Gawande,1 Nandadeva Yakandawala,1 Karen LoVetri,1 George G. Zhanel,2 Tony Romeo,3 Albert D. Friesen,4 and Srinivasa Madhyastha1*

Kane Biotech Inc., Winnipeg, MB, Canada,1 Medical Microbiology, University of Manitoba, Health Science Centre, MS673-820 Sherbrook St., Winnipeg, MB, Canada R3A 1R9,2 Department of Microbiology and Immunology, Emory University School of Medicine, 3105 Rollins Research Centre, 1510 Clifton Rd. NE, Atlanta, Georgia 30322,3 Medicure Inc., 4-1200 Waverley Street, Winnipeg, MB, Canada, R3T 0P44

Received 11 October 2005/ Returned for modification 22 January 2006/ Accepted 6 February 2006

The colonization of uropathogenic bacteria on urinary catheters resulting in biofilm formation frequently leads to the infection of surrounding tissue and often requires removal of the catheter. Infections associated with biofilms are difficult to treat since they may be more than 1,000 times more resistant to antibiotics than their planktonic counterparts. We have developed an antibiofilm composition comprising an N-acetyl-D-glucosamine-1-phosphate acetyltransferase (GlmU) inhibitor and protamine sulfate, a cationic polypeptide. The antibiofilm activity of GlmU inhibitors, such as iodoacetamide (IDA), N-ethyl maleimide (NEM), and NEM analogs, including N-phenyl maleimide, N,N'-(1,2-phenylene)dimaleimide (oPDM), and N-(1-pyrenyl)maleimide (PyrM), was tested against that of catheter-associated uropathogens. Both IDA and NEM inhibited biofilm formation in Escherichia coli. All NEM analogs showed antibiofilm activity against clinical isolates of E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus epidermidis, and Enterococcus faecalis. The combination of oPDM with protamine sulfate (PS) enhanced its antibiofilm activity and reduced its effective concentration to as low as 12.5 µM. In addition, we found that the in vitro inhibitory activity of oPDM-plus-PS-coated silicone catheters against P. aeruginosa and S. epidermidis colonization was superior to that of catheters coated with silver hydrogel. Confocal scanning laser microscopy further confirmed that the oPDM-plus-PS-coated silicone catheters were almost free from bacterial colonization. Thus, a broad-spectrum antibiofilm composition comprising a GlmU inhibitor and protamine sulfate shows promise for use in anti-infective coatings for medical devices, including urinary catheters.

* Corresponding author. Mailing address: Kane Biotech Inc., 5-1250 Waverley Street, Winnipeg, MB, Canada R3T 6C6. Phone: (204) 453-1301, ext. 235. Fax: (204) 453-1314. E-mail: srim{at}kanebiotech.com.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1835-1840, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1835-1840.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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