Accelerating growth and global expansion of antimicrobial resistance has deepened the need for discovery of novel antimicrobial agents. Antimicrobial peptides have clear advantages over conventional antibiotics which include slower emergence of resistance, broad-spectrum antibiofilm activity, and the ability to favourably modulate the host immune response. Broad bacterial susceptibility to antimicrobial peptides offers an additional tool to expand knowledge about the evolution of antimicrobial resistance. Structural and functional limitations, combined with a stricter regulatory environment, have hampered the clinical translation of antimicrobial peptides as potential therapeutic agents. Existing computational and experimental tools attempt to ease the preclinical and clinical development of antimicrobial peptides as novel therapeutics. This Review identifies the benefits, challenges, and opportunities of using antimicrobial peptides against multidrug-resistant pathogens, highlights advances in the deployment of novel promising antimicrobial peptides, and underlines the needs and priorities in designing focused development strategies taking into account the most advanced tools available.

The value of antimicrobial peptides in the age of resistance

More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide's structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

Antimicrobial Peptides: Mechanisms of Action and Resistance:

Peptide Design Principles for Antimicrobial Applications.

Current research has demonstrated that small cationic amphipathic peptides have strong potential not only as antimicrobials, but also as antibiofilm agents, immune modulators, and anti-inflammatories. Although traditionally termed antimicrobial peptides (AMPs) these additional roles have prompted a shift in terminology to use the broader term host defense peptides (HDPs) to capture the multi-functional nature of these molecules. In this review, we critically examined the role of AMPs and HDPs in infectious diseases and inflammation. It is generally accepted that HDPs are multi-faceted mediators of a wide range of biological processes, with individual activities dependent on their polypeptide sequence. In this context, we explore the concept of chemical space as it applies to HDPs and hypothesize that the various functions and activities of this class of molecule exist on independent but overlapping activity landscapes. Finally, we outline several emerging functions and roles of HDPs and highlight how an improved understanding of these processes can potentially be leveraged to more fully realize the therapeutic promise of HDPs.

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Reassessing the Host Defense Peptide Landscape

Small open reading frames (smORFs) of 100 codons or fewer are usually - if arbitrarily - excluded from proteome annotations. Despite this, the genomes of many metazoans, including humans, contain millions of smORFs, some of which fulfil key physiological functions. Recently, the transcriptome of Drosophila melanogaster was shown to contain thousands of smORFs of different classes that actively undergo translation, which produces peptides of mostly unknown function. Here, we present a comprehensive analysis of smORFs in flies, mice and humans. We propose the existence of several functional classes of smORFs, ranging from inert DNA sequences to transcribed and translated cis-regulators of translation and peptides with a propensity to function as regulators of membrane-associated proteins, or as components of ancient protein complexes in the cytoplasm. We suggest that the different smORF classes could represent steps in gene, peptide and protein evolution. Our analysis introduces a distinction between different peptide-coding classes of smORFs in animal genomes, and highlights the role of model organisms for the study of small peptide biology in the context of development, physiology and human disease.

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Classification and function of small open reading frames

The growing problem of antibiotic-resistant microorganisms results in an urgent need for substitutes to conventional antibiotics with novel modes of action and effective activities. Antimicrobial peptides (AMPs), produced by a wide variety of living organisms acting as a defense mechanism against invading pathogenic microbes, are considered to be such promising alternatives. AMPs display a broad spectrum of antimicrobial activity and a low propensity for developing resistance. Therefore, a thorough understanding of AMPs is essential to exploit them as antimicrobial drugs. Considering this, we developed a comprehensive user-friendly data repository of antimicrobial peptides (DRAMP), which holds 17349 antimicrobial sequences, including 4571 general AMPs, 12704 patented sequences and 74 peptides in drug development. Entries in the database have detailed annotations, especially detailed antimicrobial activity data (shown as target organism with MIC value) and structure information. Annotations also include accession numbers crosslinking to Pubmed, Swiss-prot and Protein Data Bank (PDB). The website of the database comes with easy-to-operate browsing as well as searching with sorting and filtering functionalities. Several useful sequence analysis tools are provided, including similarity search, sequence alignment and conserved domain search (CD-Search). DRAMP should be a useful resource for the development of novel antimicrobial peptide drugs.

Meifeng Zhou

Papers

DRAMP: a comprehensive data repository of antimicrobial peptides.