pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18703-8. doi: 10.1073/pnas.1422091112. Epub 2014 Dec 15.

Abstract

The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.

Keywords: Pseudomonas aeruginosa; Staphylococcus aureus; cathelicidin; cystic fibrosis; host defense.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / pharmacology*
  • Antimicrobial Cationic Peptides / agonists
  • Antimicrobial Cationic Peptides / pharmacology*
  • Drug Synergism
  • Humans
  • Hydrogen-Ion Concentration
  • Pseudomonas aeruginosa / growth & development*
  • Staphylococcus aureus / growth & development*
  • beta-Defensins / agonists
  • beta-Defensins / pharmacology*

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • DEFB103A protein, human
  • beta-Defensins
  • CAP18 lipopolysaccharide-binding protein