title: Antibiofilm activity of GlmU enzyme inhibitors against catheter-associated uropathogens.
abstract: 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 microM. 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.
authors.affiliation: Kane Biotech Inc., 5-1250 Waverley Street, Winnipeg, Manitoba, Canada R3T 6C6.
authors.forename: Euan
authors.initials: E
authors.lastname: Burton
authors.forename: Purushottam V
authors.initials: PV
authors.lastname: Gawande
authors.forename: Nandadeva
authors.initials: N
authors.lastname: Yakandawala
authors.forename: Karen
authors.initials: K
authors.lastname: LoVetri
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Tony
authors.initials: T
authors.lastname: Romeo
authors.forename: Albert D
authors.initials: AD
authors.lastname: Friesen
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Madhyastha
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D018441:Biofilms; D002408:Catheters, Indwelling / Q000382:microbiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D018613:Microscopy, Confocal; D011479:Protamines / Q000494:pharmacology; D014546:Urinary Catheterization / Q000009:adverse effects; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D023181:Antimicrobial Cationic Peptides; D004791:Enzyme Inhibitors; D011479:Protamines; D000123:Acetyltransferases; C428383:glucosamine-1-phosphate acetyltransferase