Abstract
Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3–9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible Escherichia coli and restore antibiotic activity against a multi-drug resistant E. coli strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the E. coli RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs.
Highlights
Antibiotic resistance is a growing global emergency, with few novel antibiotics on the horizon
Our previous investigation of the sequences and conformations of a library of cationic antimicrobial peptide structures highlighted the importance of alternating basic and aromatic amino acid residues [1]. This is thought to be important in allowing the peptides to assume the amphipathic conformation that is required for them to interact with the bacterial membrane
A series of peptides was designed to incorporate the residues required for amphipathic conformation and potential efflux pump binding
Summary
Antibiotic resistance is a growing global emergency, with few novel antibiotics on the horizon. Our previous investigation of the sequences and conformations of a library of cationic antimicrobial peptide structures highlighted the importance of alternating basic and aromatic amino acid residues [1]. This is thought to be important in allowing the peptides to assume the amphipathic conformation that is required for them to interact with the bacterial membrane. The pairing of basic and aromatic residues could mimic the structure of the RND efflux pump inhibitor phenylalanine-arginine-β-naphthylamide (PAβN), which follows a similar aromatic-basic-aromatic motif [4] This led to the hypothesis that small peptides with such alternating amino acid sequences could potentially retain antimicrobial activity whilst overcoming a major resistance mechanism. With these features in mind, a series of short peptides was designed to test our hypothesis
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