Antimicrobial Peptides: An Emerging Category of Therapeutic Agents

Abstract

Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

Keywords: AMP; anti-infectives; antibiotic resistance; antimicrobial peptide; therapeutic agents.

Figure 1

Published research on AMPs identified from 2004 until September 2016. Article counts were carried out after searching in PubMed using the following key words: antimicrobial peptides, AMPs, and/or host defense peptides. The search results demonstrate that in the last decade the AMP research field has progressively expanded as represented by the continuous increase in the number of articles. Q, quarter.

Figure 2

Peptides representing the three main categories of the secondary structures of AMPs. LL-37 and human lactoferricin represent α-helical peptides, human β-defensin 1 represents β-sheet peptides, and indolocidin represents extended/random-coil structures. Structures are from Protein Data Bank in Europe (PDB id codes 2k6o, 1z6v, 1kj5, and 1g89).

Figure 3

Schematic illustration of bacterial killing mechanisms by AMPs.

Figure 4

Schematic illustration of immunomodulatory activities of AMPs. Pathogen recognition via pathogen recognition receptors (PRRs), such as TLRs, by epithelial cells, macrophages, and dendritic cells, leads to killing via phagocytosis as well as release of proinflammatory cytokines and chemokines by these cells, that subsequently stimulates the recruitment of additional immune cells to the site of infection. In addition, pathogen insult will lead to maturation of dendritic cells and subsequent initiation of adaptive immunity. AMPs indirectly promote pathogen clearance by stimulating chemotaxis and immune cell differentiation, while also preventing harmful inflammation and sepsis by inhibition of proinflammatory cytokine release and direct scavenging of bacterial endotoxins such as LPS. Up- or down-regulation of responses by AMPs is indicated by green arrows.