Optimizing Exogenous Surfactant as a Pulmonary Delivery Vehicle for Chicken Cathelicidin-2

Brandon Baer, Edwin J. A. Veldhuizen, Natalia Molchanova, Shehrazade Jekhmane, Markus Weingarth, Håvard Jenssen, Jennifer S. Lin, Annelise E. Barron, Cory Yamashita, Ruud Veldhuizen

Research output: Contribution to journalJournal articlepeer-review

Abstract

The rising incidence of antibiotic-resistant lung infections has instigated a much-needed search for new therapeutic strategies. One proposed strategy is the use of exogenous surfactants to deliver antimicrobial peptides (AMPs), like CATH-2, to infected regions of the lung. CATH-2 can kill bacteria through a diverse range of antibacterial pathways and exogenous surfactant can improve pulmonary drug distribution. Unfortunately, mixing AMPs with commercially available exogenous surfactants has been shown to negatively impact their antimicrobial function. It was hypothesized that the phosphatidylglycerol component of surfactant was inhibiting AMP function and that an exogenous surfactant, with a reduced phosphatidylglycerol composition would increase peptide mediated killing at a distal site. To better understand how surfactant lipids interacted with CATH-2 and affected its function, isothermal titration calorimetry and solid-state nuclear magnetic resonance spectroscopy as well as bacterial killing curves against Pseudomonas aeruginosa were utilized. Additionally, the wet bridge transfer system was used to evaluate surfactant spreading and peptide transport. Phosphatidylglycerol was the only surfactant lipid to significantly inhibit CATH-2 function, showing a stronger electrostatic interaction with the peptide than other lipids. Although diluting the phosphatidylglycerol content in an existing surfactant, through the addition of other lipids, significantly improved peptide function and distal killing, it also reduced surfactant spreading. A synthetic phosphatidylglycerol-free surfactant however, was shown to further improve CATH-2 delivery and function at a remote site. Based on these in vitro experiments synthetic phosphatidylglycerol-free surfactants seem optimal for delivering AMPs to the lung.
Original languageEnglish
Article number9392
JournalScientific Reports
Volume2020
Issue number10
ISSN2045-2322
DOIs
Publication statusPublished - 2020

Keywords

  • Bacterial infection
  • Clinical pharmacology
  • Diseases
  • Drug delivery
  • Drug discovery and development
  • Infectious diseases
  • Lipids
  • Peptides
  • Pharmacology
  • Proteins
  • Respiratory tract diseases
  • Solid-state NMR

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