In cystic fibrosis lungs, the natural antimicrobial peptide LL‑37 gets stuck in sticky bundles made of DNA and filamentous actin, which blocks its ability to kill bacteria. Enzymes or chemicals that break down DNA or actin (like the CF drug Dornase alfa, gelsolin, or polyaspartate) free LL‑37, letting it move into the fluid part of sputum where it can work. Bacterial LPS also ties up LL‑37, but a special LPS‑binding peptide can stop that interaction.

Cationic antibacterial peptides (ABPs) are secreted in the airways and function in the first line of defence against infectious agents. They attack multiple molecular targets to cooperatively penetrate and disrupt microbial surfaces and membrane barriers. Antibacterial properties of ABPs, including cathelicidin LL-37, are reduced in cystic fibrosis (CF) airways as a result of direct interaction with DNA and filamentous (F)-actin. Microscopic evaluation of a mixed solution of DNA and F-actin, after the addition of rhodamine-B-labelled LL-37 peptide, revealed the presence of a bundle structure similar to that present in CF sputum. Analysis of CF sputum after centrifugation showed that LL-37 was mostly bound to components of the pellet fraction containing DNA, F-actin and cell remnants. Factors that dissolve DNA/actin bundles and fluidise CF sputum, such as Dornase alfa (recombinant human DNase I), gelsolin, polyaspartate or their combinations, increased the amount of LL-37 peptide detected in the supernatant of CF sputum. The presence of the bacterial endotoxin lipopolysaccharide (LPS) in CF sputum and the ability of LPS to inhibit the antibacterial activity of LL-37 suggests that inactivation of LL-37 function in CF sputum partially results from its interaction with LPS. LL-37-LPS interaction was prevented by an LPS-binding protein (LBP)-derived peptide known for its ability to neutralise LPS, whereas LBPW91A, a mutant peptide that lacks ability to bind LPS, had no effect. A combination of factors that dissolve DNA/filamentous-actin aggregates together with lipopolysaccharide-binding agents may represent a potential treatment for the chronic infections that occur in cystic fibrosis airways.