This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project will systematically test the hypothesis that the antibacterial properties of genetically engineered human lysozyme (hLYS) acting on P. aeruginosa biofilms is enhanced by synergistic interactions with antimicrobial peptides, human lactoferrin, and/or Meveol. Chronic infection of the lower respiratory tract results in accumulation of extracellular, anionic, biopolymers such as DNA, F-actin, mucins, and in the case of mucoid P. aeruginosa infections, the exopolysaccharide alginate. The high local concentrations of these biopolymers in the infected airway are believed to inhibit cationic antimicrobial peptides and proteins, and are particularly problematic with respect to human lysozyme (hLYS) function. We have successfully re-engineered hLYS's electrostatic potential to produce enzyme variants with enhanced bactericidal activity in the presence of clinically relevant inhibitory biopolymers (2). Preliminary animal studies have indicated that at least one enhanced human lysozyme (EhLYS), when compared against the wild type protein or PBS controls, reduces P. aeruginosa burden in a mouse model of lung infection. Extending this research to have greater clinical impact, we hypothesize here that the anti-Pseudomonal activity of this enzyme will be substantially improved by co-administration with complementary antibacterial peptides, the antibacterial protein human lactoferrin, or Meveol.
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