A frog skin-derived antimicrobial peptide against Pseudomonas aeruginosa-induced infections

P. aeruginosa is the most prevalent bacterium causing mucosal surface infections such as those found in the lungs of cystic fibrosis sufferers or associated with contact lens wear resulting in bacterial keratitis [1]. The growing emergence of multidrug-resistant strains calls for the discovery of new antibiotics with new modes of action. Naturally occurring antimicrobial peptides (AMPs) hold promise as new therapeutics [2]. They are produced by almost all forms of life as key components of the innate immune response [3]. Unlike conventional antibiotics, most AMPs interact with and increase the permeability of the microbial membrane as part of their killing mechanism [4]. Amphibian skin secretions are one of the richest sources for AMPs, which are synthesized and stored within granules of holocrine-type serous glands and released upon stimulation [6-8]. Here we investigated the anti-Pseudomonal efficacy of a frog skin-derived AMP, Esculentin(1-21) [Esc(1-21)], in vitro and in mouse models of lung/ocular Pseudomonas infections [5]. Our results revealed that Esc(1-21) has (i) a rapid anti-Pseudomonal activity against both free-living and biofilm forms of this pathogen, with a membrane-perturbing activity as a plausible mode of action. This limits the emergence of resistance; (ii) the capability to preserve its bactericidal activity under physiological conditions that better mimic the lung/ocular surface milieu (i.e. in the presence of high salt concentration and/or tears); (iii) the ability to neutralize the toxic effect of bacterial lipopolysaccharide and (iv) the ability to induce migration of epithelial cells in a wound healing assay. Regarding in vivo studies, Esc(1-21) has been found to promote survival in mouse models of P. aeruginosa-induced pulmonary infections by reducing the number of colony counts within the lungs, after a single intratracheal administration. In addition, it has been shown to significantly reduce the level of ocular infection in murine models of P. aeruginosa keratitis, upon topical treatment, three times/day for up to 5 days post-infection and to reduce the amount of viable bacterial cells and neutrophil infiltration within the cornea, compared to PBS treated animals. Overall, Esc(1-21) has great potential for development as a novel pharmaceutical for the treatment of Pseudomonas-induced pneumonia or keratitis upon local application to the site of infection. 1. Kolar SS and McDermott AM. Cell Mol Life Sci (2011); 68:2201-13 2. Mookherjee, N., and Hancock, R. E. Cell Mol Life Sci(2007); 64, 922-933 3. Boman H.G. Annu. Rev. Immunol. (1995); 13:61-92. 4.Shai, Y. Biochim. Biophys. Acta(1999); 1462, 55–70 5. Luca V et al. Cell Mol Life Sci(2013); 70:2773-86