Antimicrobial Peptide Therapeutics for Cystic Fibrosis

Abstract

Greater than 90% of lung infections in cystic fibrosis (CF) patients are caused by Pseudomonas aeruginosa, and the majority of these patients subsequently die from lung damage. Current therapies are either targeted at reducing obstruction, reducing inflammation, or reducing infection. To identify potential therapeutic agents for the CF lung, 150 antimicrobial peptides consisting of three distinct structural classes were screened against mucoid and multidrug-resistant clinical isolates of P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus. Five peptides that retained potent antimicrobial activities in physiological salt and divalent cation environment were further characterized in vivo using a rat chronic lung infection model. All animals were inoculated intratracheally with 10 4 P. aeruginosa mucoid PAO1 cells in agar beads. Three days following inoculation treatment was initiated. Animals were treated daily for 3 days with 100 l of peptide solution (1 mg/ml) in 10 mM sodium citrate, which was deposited via either intratracheal instillation or aerosolization. Control animals received daily exposure to vehicle alone. At the end of the treatment the lungs of the animals were removed for quantitative culture. Four peptides, HBCM2, HBCM3, HBCP␣-2, and HB71, demonstrated significant reduction in Pseudomonas bioburden in the lung of rats. Further in vivo studies provided direct evidence that anti-inflammatory activity was associated with three of these peptides. Therefore, small bioactive peptides have the potential to attack two of the components responsible for the progression of lung damage in the CF disease: infection and inflammation.

Contributions of two UDP-glucose dehydrogenases to viability and polymyxin B resistance of Burkholderia cenocepacia

“…They are part of the innate immune response (Ganz, 2003;Zanetti, 2004) and have been shown to kill bacteria through the disruption of the inner membrane (Brogden, 2005) and also through inhibition of intracellular processes (Patrzykat et al, 2002). APs have been proposed as agents for treatment of infections by other CF lung pathogens, such as Pseudomonas aeruginosa (Zhang et al, 2005). Unfortunately, due to the extraordinary resistance of B. cenocepacia to the killing effects of APs, they are unlikely to be useful agents for treatment of lung infections by B. cenocepacia.…”

Activity of tick antimicrobial peptide from Ixodes persulcatus (persulcatusin) against cell membranes of drug-resistant Staphylococcus aureus

“…[22][23][24] Conversely, there are reports that passage under sub-MIC concentrations produced lesser increases in experimental MIC for antimicrobial peptides than conventional antimicrobial agents, and no cross-resistance has been observed among different antimicrobial peptides. 25,26 Thus, it is expected that bacteria will find it difficult to acquire resistance to antimicrobial peptides. 22,27 Antimicrobial peptides interact with bacteria by electrostatic forces between their positive amino acid residues and negative charges present on the bacterial cell surface, thereby causing damage to the cell membrane.…”

Human Defensins: Potential Tools for Clinical Applications

“…Antimicrobial peptides have been successfully applied in cystic fibrosis. They were applied via aerosolization [92]. Vector-based mediated delivery of gene encoding for antimicrobial peptides were used in cancer therapy [93].…”

“…As several studies have shown that no bacterial or viral resistance against AMPs has developed so far [42][43][44], antimicrobial peptides could be a powerful tool in the therapy of acute or chronic infectious diseases in the future. As there is a growing number of treatment-resistant bacteria and viruses causing immense problems and exploding costs in public healthcare (Figure 3), it is a promising therapeutic concept to develop treatments involving the application of these molecules, sole or in combination with conventional antibiotics.…”