Design of α-helical antimicrobial peptides with a high selectivity index

ABSTRACT

Introduction: Low-molecular-weight antibiotics are gradually rendered ineffective by multidrug-resistant bacteria. Promising replacements are fast-acting antimicrobial peptides, either found as host defense peptides or designed, but their main weakness in applications is low selectivity for bacterial cells.

Areas covered: This paper explores how much human design has improved the evolutionary design for linear alpha-class antimicrobial peptides with a selective antibacterial activity. Activity data against E. coli and S. aureus are collected from numerous publications reporting the hemolytic activity as well. Overall performance parameters are defined for easier ranking of best-performing peptides.

Expert opinion: Connecting structure to the specific activity of antimicrobial peptides should include considerations of which peptide features channel adaptable conformational changes toward pore-inducing interactions with anionic membranes. Imperfect amphipathicity, enhanced flexibility, self-assembly potential, and an oblique, only partially helical structure, can improve structure-activity and structure-selectivity relationships. The number of optimal combinations of antimicrobial activity and low toxicity are immense when dedicated databases are constructed, the best descriptors extracted and followed through model building, simulations, and selectivity predictions, with everything tightly connected to feedback cycles of in vitro testing.

KEYWORDS:

• Design
• antimicrobial peptides
• selectivity
• prediction

Article highlights

• Natural and designed antimicrobial peptides are ranked according to their selectivity index and overall performance against standard E. coli and S. aureus strains.

• Helix-hinge-helix structure is a frequent feature for longer peptides with promising antibacterial selectivity, which can span the membrane.

• Sequence profile of hydrophobic moments can often be used for a quick indication that a peptide may form such a structure at the membrane surface.

• For shorter peptides, the human design produced a greater number of lead sequences superior to natural in antibacterial activity and selectivity.

• A design driven by simulations of dipole moments, quadrupole moments, and 3D moments during dynamic peptide-lipid interactions can help in getting promising leads for human needs.

• Currently underexplored is the design of conformationally flexible peptides induced by anionic membranes to change the bilayer structure by self-association and interaction with specific polar lipids.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.