The lexicon of antimicrobial peptides: a complete set of arginine and tryptophan sequences

Lynda K Harris,Curtis B Dobson,Christopher G Knight,Thomas A Jowitt,Sam Clark

doi:10.1038/s42003-021-02137-7

Abstract

Our understanding of the activity of cationic antimicrobial peptides (AMPs) has focused on well-characterized natural sequences, or limited sets of synthetic peptides designed de novo. We have undertaken a comprehensive investigation of the underlying primary structural features that give rise to the development of activity in AMPs. We consider a complete set of all possible peptides, up to 7 residues long, composed of positively charged arginine (R) and / or hydrophobic tryptophan (W), two features most commonly associated with activity. We found the shortest active peptides were 4 or 5 residues in length, and the overall landscapes of activity against gram-positive and gram-negative bacteria and a yeast were positively correlated. For all three organisms we found a single activity peak corresponding to sequences with around 40% R; the presence of adjacent W duplets and triplets also conferred greater activity. The mechanistic basis of these activities comprises a combination of lipid binding, particularly to negatively charged membranes, and additionally peptide aggregation, a mode of action previously uninvestigated for such peptides. The maximum specific antimicrobial activity appeared to occur in peptides of around 10 residues, suggesting ‘diminishing returns’ for developing larger peptides, when activity is considered per residue of peptide.

Highlights

Our understanding of the activity of cationic antimicrobial peptides (AMPs) has focused on well-characterized natural sequences, or limited sets of synthetic peptides designed de novo
We have previously reported that the self-aggregating amyloid β (Aβ) peptide associated with senile plaques in Alzheimer’s disease (AD) is upregulated in response to infection[18], and others report that it may function as a conventional AMP19,20
Our approach of characterising the biological activity of all possible peptides up to seven residues comprising R and W, enables us to make some general conclusions about the rules governing the activity of synthetic AMPs comprising cationic and hydrophobic residues

Summary

Introduction

Our understanding of the activity of cationic antimicrobial peptides (AMPs) has focused on well-characterized natural sequences, or limited sets of synthetic peptides designed de novo. 1234567890():,; Antimicrobial peptides (AMPs) are short amino acid sequences that kill or inhibit the growth of microorganisms[1], and which have diverse and broad mechanisms of action They occur naturally as a component of innate immunity, and are produced widely by many diverse organisms[2,3], they can be designed de novo from natural or non-natural amino acids[4,5,6]. Perturbing the bacterial cytoplasmic membrane is the most commonly studied mode of action for AMPs, including short cationic peptides[15] This can occur through a number of proposed mechanisms, including the barrel stave and toroidal pore models, in which peptide monomers insert into the membrane and form structured pores, resulting in increased lysis, or the carpet model, in which peptides accumulate on the bacterial surface, causing stress on the membrane, which tears causing lipid removal[5,16]

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