In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection

Abstract

Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1–21) and its diastereomer Esc(1–21)-1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1–21)-1c was more efficacious than Esc(1–21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1–21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infections.

Structure-function-guided exploration of the antimicrobial peptide polybia-CP identifies activity determinants and generates synthetic therapeutic candidates

“…Among the microorganisms studied, P. aeruginosa is a pathogenic Gram-negative bacterium responsible for pneumonia 76 and for infections of the urinary tract 77 , gastrointestinal tissue 78 , skin and soft tissues 79 – 81 and is very common in patients with cystic fibrosis 82 . Like other bacteria, P. aeruginosa is becoming resistant to common antibiotics 82 , and AMPs have been proposed as an alternative treatment to combat such infections 83 .…”

Frog Skin-Derived Peptides Against Corynebacterium jeikeium: Correlation between Antibacterial and Cytotoxic Activities

“…Amphibian skin secretion is considered a rich source of broad-spectrum AMPs, and over the years, numerous peptides have been isolated and classified into the corresponding families, such as esculentins, temporins, and bombinins H [32,33]. Recently, we characterized the potent effectiveness of two derivatives of the N-terminal part of two frog skin AMPs, i.e., esculentin-1a and -1b, namely esculentin-1a(1-21) (Esc(1-21)) and esculentin-1b(1-18) (Esc(1-18)), respectively, especially against alarming human pathogens, such as Pseudomonas aeruginosa and Candida albicans, either in vitro or in vivo [34][35][36]. Here, for the first time, we explore the efficacy of these two alpha-helical peptides against C. jeikeium by determining their minimum inhibitory concentrations (MIC) and compare this activity with that of other peptide isoforms belonging to different AMP families (i.e., the alpha-helical temporin A, temporin B, temporin G, and bombinin H 2 ).…”

Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, α4-Short, in a Murine Model of Respiratory Infection

“…However, some topical applications in animal models in the last several years are particularly encouraging (52–56). Our group has been focusing on addressing this limitation, as demonstrated by the efficacy of engineered AMPs such as WLBU2 and natural AMPs, including frog skin-derived esculentin systemically and via direct delivery in the mouse airway (12, 23, 24, 31, 57, 58). Nevertheless, the increased host toxicity resulting from these optimization studies led us to adopt a natural template alternative, which facilitates the successful optimization of α4-short without the cytotoxicity observed in highly optimized de novo -engineered AMPs (22).…”