Abstract
Due to the growing concern about antibiotic-resistant microbial infections, increasing support has been given to new drug discovery programs. A promising alternative to counter bacterial infections includes the antimicrobial peptides (AMPs), which have emerged as model molecules for rational design strategies. Here we focused on the study of Pa-MAP 1.9, a rationally designed AMP derived from the polar fish Pleuronectes americanus. Pa-MAP 1.9 was active against Gram-negative planktonic bacteria and biofilms, without being cytotoxic to mammalian cells. By using AFM, leakage assays, CD spectroscopy and in silico tools, we found that Pa-MAP 1.9 may be acting both on intracellular targets and on the bacterial surface, also being more efficient at interacting with anionic LUVs mimicking Gram-negative bacterial surface, where this peptide adopts α-helical conformations, than cholesterol-enriched LUVs mimicking mammalian cells. Thus, as bacteria present varied physiological features that favor antibiotic-resistance, Pa-MAP 1.9 could be a promising candidate in the development of tools against infections caused by pathogenic bacteria.
Highlights
In recent decades, improvements in the prevention and treatment of infectious diseases caused by pathogenic microorganisms has been of great importance in reducing morbidity and mortality, leading to a better quality of life and longer life expectancy[1]
No antibacterial activity was observed against P. aeruginosa and S. aureus, even at the maximum concentration used for this assay (115 μ M)
Similar enhanced activities against Gram-negative strains have been reported for other anti-microbial peptides (AMPs) isolated or derived from the winter flounder P. americanus, as it is the case of pleurocidin, a cationic α -helical peptide with high activities against E. coli and Pseudomonas aeruginosa, with minimal inhibitory concentrations (MICs) values below 1 μ M16
Summary
Improvements in the prevention and treatment of infectious diseases caused by pathogenic microorganisms has been of great importance in reducing morbidity and mortality, leading to a better quality of life and longer life expectancy[1]. Cationic amphipathic peptides termed anti-microbial peptides (AMPs) have been widely investigated as a promising alternative for the treatment of infections caused by pathogenic microorganisms[5] These molecules have been isolated from a wide number of organisms including plants[6], animals[7] and bacteria[8]. Jiang and co-workers[11] have recently introduced a new concept of template-based design involving the arrangement of lysine and arginine residues in the center of the non-polar region of amphipathic α -helical AMPs in order to enhance peptide’s selectivity against both eukaryotic and prokaryotic cell membranes In addition to these strategies, biophysical studies have been used to evaluate AMP activities and design improved analogues by predicting and characterizing their structures in different environments, as well as performing molecular modelling, dynamics and docking simulations at atomic levels[5]. Biophysical experiments, using circular dichroism (CD), fluorescence spectroscopy and atomic force microscopy (AFM), in combination with in silico studies such as molecular modelling, dynamics and docking, were performed to obtain insights into the structure of Pa-MAP 1.9, as well as its mechanism of action
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