Antimicrobial Peptides and Their Therapeutic Potential for Bacterial Skin Infections and Wounds

Abstract

Alarming data about increasing resistance to conventional antibiotics are reported, while at the same time the development of new antibiotics is stagnating. Skin and soft tissue infections (SSTIs) are mainly caused by the so called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) which belong to the most recalcitrant bacteria and are resistant to almost all common antibiotics. S. aureus and P. aeruginosa are the most frequent pathogens isolated from chronic wounds and increasing resistance to topical antibiotics has become a major issue. Therefore, new treatment options are urgently needed. In recent years, research focused on the development of synthetic antimicrobial peptides (AMPs) with lower toxicity and improved activity compared to their endogenous counterparts. AMPs appear to be promising therapeutic options for the treatment of SSTIs and wounds as they show a broad spectrum of antimicrobial activity, low resistance rates and display pivotal immunomodulatory as well as wound healing promoting activities such as induction of cell migration and proliferation and angiogenesis. In this review, we evaluate the potential of AMPs for the treatment of bacterial SSTIs and wounds and provide an overview of the mechanisms of actions of AMPs that contribute to combat skin infections and to improve wound healing. Bacteria growing in biofilms are more resistant to conventional antibiotics than their planktonic counterparts due to limited biofilm penetration and distinct metabolic and physiological functions, and often result in chronification of infections and wounds. Thus, we further discuss the feasibility of AMPs as anti-biofilm agents. Finally, we highlight perspectives for future therapies and which issues remain to bring AMPs successfully to the market.

Keywords: antimicrobial peptides; bacterial resistance; bacterial toxins; biofilms; skin and soft tissue infections; topical therapy; wound healing; wounds.

Figure 1

Structure of human skin and cell types in epidermis and dermis. Skin appendages are not depicted and the list of cell types is non-exhaustive. Dendritic epidermal T cell (DETC), dermal dendritic cell (dermal DC), innate lymphoid cell (ILC), plasmacytoid dendritic cell (pDC).

Figure 2

Regulation of endogenous AMPs in different skin diseases. In psoriasis, LL-37 is forming complexes with self-DNA or -RNA, thus leading to the activation of plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) which trigger Th₁ and Th₁₇ responses by secretion of IL-12 and IL-23. Rosacea is characterized by increased TLR2 expression which triggers LL-37 production and increases protease activity leading to unusual LL-37 cleavage products. In atopic dermatitis, Th₂-derived cytokines suppress the induction of AMPs. In acne vulgaris, C. acnes (formerly P. acnes) induces up-regulation of AMPs in keratinocytes and sebocytes.

Figure 3

Possible bacterial resistance mechanisms against AMPs.

Figure 4

Proposed molecular mechanism of AMP-induced keratinocyte migration and/or proliferation via P2X7R and EGFR. AMPs induce P2X7R activation indirectly or by acting as allosteric modulators, thus increasing sensitivity of the extracellular ligand adenosine-triphosphate (ATP). P2X7R activation leads to EGFR transactivation via metalloprotease-mediated shedding of EGFR ligands which after cleavage from their membrane-anchored form trigger EGFR signaling. Activation of distinct signaling pathways finally leads to migration and/or proliferation of keratinocytes.

Figure 5

Factors most likely determining the extent of topical bioavailability of AMPs.