title: Bioengineered lysozyme in combination therapies for Pseudomonas aeruginosa lung infections.
abstract: There is increasing urgency in the battle against drug-resistant bacterial pathogens, and this public health crisis has created a desperate need for novel antimicrobial agents. Recombinant human lysozyme represents one interesting candidate for treating pulmonary infections, but the wild type enzyme is subject to electrostatic mediated inhibition by anionic biopolymers that accumulate in the infected lung. We have redesigned lysozyme's electrostatic potential field, creating a genetically engineered variant that is less susceptible to polyanion inhibition, yet retains potent bactericidal activity. A recent publication demonstrated that the engineered enzyme outperforms wild type lysozyme in a murine model of Pseudomonas aeruginosa lung infection. Here, we expand upon our initial studies and consider dual therapies that combine lysozymes with an antimicrobial peptide. Consistent with our earlier results, the charge modified lysozyme combination outperformed its wild type counterpart, yielding more than an order-of-magnitude reduction in bacterial burden following treatment with a single dose.
authors.affiliation: Thayer School of Engineering; Dartmouth University; Hanover, NH USA; Department of Biological Sciences; Dartmouth University; Hanover, NH USA; Molecular and Cellular Biology Program; Dartmouth University; Hanover, NH USA.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Griswold
authors.affiliation: University of Vermont College of Medicine; Division of Pulmonary and Critical Care Medicine; Burlington, VT USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Bement
authors.affiliation: University of Vermont College of Medicine; Division of Pulmonary and Critical Care Medicine; Burlington, VT USA.
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Teneback
authors.affiliation: Thayer School of Engineering; Dartmouth University; Hanover, NH USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Scanlon
authors.affiliation: University of Vermont College of Medicine; Microbiology and Molecular Genetics; Burlington, VT USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wargo
authors.affiliation: University of Vermont College of Medicine; Division of Pulmonary and Critical Care Medicine; Burlington, VT USA.
authors.forename: Laurie W
authors.initials: LW
authors.lastname: Leclair
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D057005:Bioengineering / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004359:Drug Therapy, Combination / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000235:genetics* / Q000627:therapeutic use*; D018410:Pneumonia, Bacterial / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D015202:Protein Engineering / Q000379:methods*; D011552:Pseudomonas Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D009113:Muramidase
keywords: Pseudomonas aeruginosa; antibiotics; biotherapeutics; cystic fibrosis; drug resistance; lung infection model; lysozyme; lytic enzymes; protein engineering