Abstract
Amphibian skin-derived antimicrobial peptides (AMPs) have attracted increasing attention from scientists because of their excellent bioactivity and low drug resistance. In addition to being the alternative choice of antibiotics or anticancer agents, natural AMPs can also be modified as templates to optimise their bioactivities further. Here, a novel dermaseptin peptide, t-DPH1, with extensive antimicrobial activity and antiproliferative activity, was isolated from the skin secretion of Phyllomedusa hypochondrialis through ‘shotgun’ cloning. A series of cationicity-enhanced analogues of t-DPH1 were designed to further improve its bioactivities and explore the charge threshold of enhancing the bioactivity of t-DPH1. The present data suggest that improving the net charge can enhance the bioactivities to some extent. However, when the charge exceeds a specific limit, the bioactivities decrease or remain the same. When the net charge achieves the limit, improving the hydrophobicity makes no sense to enhance bioactivity. For t-DPH1, the upper limit of the net charge was +7. All the designed cationicity-enhanced analogues produced no drug resistance in the Gram-negative bacterium, Escherichia coli. These findings provide creative insights into the role of natural drug discovery in providing templates for structural modification for activity enhancement.
Highlights
Natural antimicrobial peptides (AMPs), as a critical component in the fight against infectious pathogens [1], are considered to be the ideal alternative agents to traditional antibiotics due to the fact of their broad-spectrum antimicrobial activity and low potential for inducing drug resistance [2,3]
AMPs have characteristic features, including conformation, net charge, hydrophobicity and amphipathicity, all of which are associated with their ability to kill microorganisms [7]
The cDNA encoding the peptide precursor of a novel peptide was repeatedly cloned from a skin secretion cDNA library of P. hypochondrialis (Figure 1)
Summary
Natural antimicrobial peptides (AMPs), as a critical component in the fight against infectious pathogens [1], are considered to be the ideal alternative agents to traditional antibiotics due to the fact of their broad-spectrum antimicrobial activity and low potential for inducing drug resistance [2,3]. In playing an essential role in their immune systems [4], the skin secretions of amphibians are known as effective sources for AMPs [5,6] Despite their diversity, AMPs have characteristic features, including conformation, net charge, hydrophobicity and amphipathicity, all of which are associated with their ability to kill microorganisms [7]. The cationic AMP molecules initially associate with the anionic phospholipids and acidic polymers of the cell membrane through electrostatic interaction [10]. These AMPs adopt amphiphilic secondary α-helix conformations.
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