title: Development of a poly(ether urethane) system for the controlled release of two novel anti-biofilm agents based on gallium or zinc and its efficacy to prevent bacterial biofilm formation.
abstract: Traditional antibiotic therapy to control medical device-based infections typically fails to clear biofilm infections and may even promote the evolution of antibiotic resistant species. We report here the development of two novel antibiofilm agents; gallium (Ga) or zinc (Zn) complexed with protoporphyrin IX (PP) or mesoprotoporphyrin IX (MP) that are both highly effective in negating suspended bacterial growth and biofilm formation. These chelated gallium or zinc complexes act as iron siderophore analogs, supplanting the natural iron uptake of most bacteria. Poly (ether urethane) (PEU; Biospan®) polymer films were fabricated for the controlled sustained release of the Ga- or Zn-complexes, using an incorporated pore-forming agent, poly(ethylene glycol) (PEG). An optimum formulation containing 8% PEG (MW=1450) in the PEU polymer effectively sustained drug release for at least 3months. All drug-loaded PEU films exhibited in vitro ≥ 90% reduction of Gram-positive (Staphylococcus epidermidis) and Gram-negative (Pseudomonas aeruginosa) bacteria in both suspended and biofilm culture versus the negative control PEU films releasing nothing. Cytotoxicity and endotoxin evaluation demonstrated no adverse responses to the Ga- or Zn-complex releasing PEU films. Finally, in vivo studies further substantiate the anti-biofilm efficacy of the PEU films releasing Ga- or Zn- complexes.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Ma
authors.forename: Erica T
authors.initials: ET
authors.lastname: Darmawan
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: James D
authors.initials: JD
authors.lastname: Bryers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D056831:Coordination Complexes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005260:Female; D005708:Gallium / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011140:Polyurethanes / Q000737:chemistry*; D016459:Prosthesis-Related Infections / Q000517:prevention & control*; D011524:Protoporphyrins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D003692:Delayed-Action Preparations; D011140:Polyurethanes; D011524:Protoporphyrins; C115016:polyetherurethane; C028025:protoporphyrin IX; D005708:Gallium; D015032:Zinc
keywords: Anti-biofilm biomaterials; Interrupting iron metabolism