1. Biotech

Medical Applications of Antimicrobial Peptides

Disclaimer: This is a user generated content submitted by a member of the WriteUpCafe Community. The views and writings here reflect that of the author and not of WriteUpCafe. If you have any complaints regarding this post kindly report it to us.

Antimicrobial peptides mainly carry out non-specific rapid killing and intracellular interference on the cell membrane of harmful pathogens and do not target specific molecular pathways, which greatly reduces the probability of bacterial resistance to antimicrobial peptides. Therefore, it is of great significance to apply antimicrobial peptides to the clinical research of antimicrobial drugs. In most cases, antimicrobial peptides themselves are often used as active ingredients (not carriers) of antibacterial and anti-inflammatory drugs, which can be used for research and testing with the ultimate purpose of human treatment by smearing or injection. Currently, DaptomycinVancomycinDalbavancin (BI397, Dalvance, Xydalba), and Colistin have been approved by the US Food and Drug Administration (FDA) for antimicrobial therapy in the form of intravenous injection. Several other antimicrobial peptides are under clinical development. In addition to their initial antibacterial effects, more and more antimicrobial peptides show multiple functions, including anti-cancer, immunomodulatory, antiviral, and anti-parasitic, etc. They also begin to be combined with medical biomaterials to serve medical tissue engineering, drug delivery, and medical cosmetology. These attempts open up a new field of application for antimicrobial peptides.

AMPs Indication Delivery Status Clinical trial identifiers
Daptomycin Bacterial skin infections Intravenous Approved NCT01211470
Vancomycin Staphylococcal infections Intravenous Approved NCT00175370
Dalbavancin (B1397, Dalvance, Xydalba) Acute bacterial skin infections Intravenous Approved NCT03233438
Colistin Multidrug-resistant Gram-negative infections Intravenous Approved NCT03397914

Fig 1. FDA-approved antimicrobial peptides1

Medical applications

1. Antibacterial and anti-inflammatory drugs

Most antimicrobial peptides have been developed as potential antibacterial and anti-inflammatory drugs. Bacteriocin is a kind of cationic antimicrobial peptide formed by 30~60 amino acid residues isolated from bacteria. Nisin, a member of the family, has high antibacterial activity against a variety of gram-positive and even gram-negative bacteria, and can also control the growth of enterotoxigenic Escherichia coli in combination with cinnamaldehyde and Ethylenediaminetetraacetic acid (EDTA).

In addition to antibacterial activity, some antimicrobial peptides can also directly or indirectly participate in host immune regulation and protect the host from infection. Defensin is another big family of antibacterial peptides widely existing in neutrophils, macrophages, lymphocytes, NK cells, and other immune cells, and has a strong pro-inflammatory function. Human defensin HBD2, HBD3, and HBD4 can stimulate the expression of IL-6, IL-10, and other immune factors in human keratinocytes. These defensins are also found to induce intracellular signaling molecules involved in keratinocyte migration and proliferation, such as EGFR, STAT 1, and phosphorylated STAT3, and promote keratinocyte migration and proliferation to participate in wound healing.

2. Antiviral drugs

In addition to anti-inflammation and immune regulation, some antimicrobial peptides have broad-spectrum resistance to viruses, typically LL-37. Barlow et al. evaluated that LL-37 could reduce the disease severity and viral replication ability of influenza virus-infected mice, and its therapeutic effect was similar to that of the specific antiviral drug Zanamivir. Tripathi et al. found that LL-37 could directly destroy the membrane structure of the influenza virus to achieve virus suppression. LL-37 also inhibited other viruses with membranous structures, such as human immunodeficiency virus (HIV), vaccinia virus, herpes simplex virus, and Dengue virus. In addition, Todorov et al. isolated a novel broad-spectrum antimicrobial peptide with the size of 3950 Da, which was resistant to herpes simplex virus, poliovirus, and measles virus while inactivating many harmful bacteria. Recent studies have also shown that the antimicrobial peptide Nisin can also interact with cell receptors targeted by the spike protein of the novel coronavirus SARS-CoV-2, opening up the prospect of using AMPs against the novel pandemic coronavirus.

3. Anti-parasitic drugs

Reports on anti-parasitic antimicrobial peptides are rare, mostly focusing on anti-plasmodium, anti-leishmania, and anti-Trypanosoma. Halictine-2, Dragomide E, Temporin-Sha, BmajPLA2-Ⅱ, and other antimicrobial peptides from different sources have strong anti-leishmania abilities. In addition, Lc-P5L4 from Larimichthys crocea can stimulate the cell membrane rupture of the Marine fish parasite Cryptocaryon. LZ1, a peptide derived from snake antimicrobial peptide, can strongly inhibit plasmodium falciparum in blood by specifically inhibiting the production of adenosine triphosphate (ATP) in plasmodium-infected red blood cells.

4. Anti-cancer drugs

Some antimicrobial peptides were also found to be resistant to some cancer cells and could be used as potential new anti-cancer drugs. Compared with normal cells, the anion composition on the surface of the cancer cell membrane is the specific target of an antibacterial peptide attack. Antimicrobial peptides are more likely to disengage from the surface of the cancer cells and selectively kill cancer cells through electrostatic action, but most antimicrobial peptides prefer to regulate the metabolic pathways or cytokines of cancer cells to achieve the anti-cancer effect.

5. Medical tissue engineering

To avoid immunogenicity and other factors, most of the antimicrobial peptides applied in the field of medical tissue engineering are LL-37 derived from human and human defensin, and most of them are chemically fixed or physically mixed with various medical devices, internal implants, drug carriers, medical consumables, and trauma dressings. At present, tissue engineering scaffolds combined with antimicrobial peptides have been used in the repair of bone, teeth, skin, cornea, and many other organs and tissues.

Additionally, LL-37 also plays an important role in cell migration, cytokine production, apoptosis, and angiogenesis. In vitro and in vivo studies of mesenchymal stem cells and LPS-induced mouse cranial lytic bone defect models showed that LL-37 effectively inhibited LPS-induced osteoclast formation and harmful bacterial activity in vitro. Similarly, the functionalization of bone morphogenetic protein-2 (BMP-2) and ponericin G1 of the three-dimensional PLGA porous scaffold can be achieved by polydopamine coating. The scaffold can effectively regulate the osteogenic differentiation of preosteoblasts and inhibit pathogenic microorganisms at the same time, thus increasing biological activity. In addition to PLGA, the antimicrobial peptide LF1-11 can also be modified on the titanium alloy surface implant, which not only greatly improves the adhesion ability of mesenchymal stem cells (due to the addition of RGD sequence) but also has an effective antibacterial effect on Staphylococcus aureus.

6. Drug delivery system

Since most antimicrobial peptides are proteins or peptides in nature, they are easy to be degraded by proteases during drug administration and some antimicrobial peptides have non-specific cytotoxicity, which can inhibit or even kill tumor cells and normal cells at the same time, limiting the clinical promotion of this kind of antimicrobial peptides. Therefore, by drug delivery system, nano-sized carriers can be used to load concentrated antimicrobial peptides to reduce the release of drugs during transportation and avoid protease degradation to a certain extent, improving the resistance and targeting ability of some antimicrobial peptides to cancer cells, bacteria or fungi. At present, the nanocarriers combined with antimicrobial peptides include biodegradable biomolecules, liposomes, and non-degradable magnetic nanoparticles.

7. Skin care and medical beauty

Some antimicrobial peptides can induce endothelial cell growth, promote the secretion of angiogenic factors, weaken vascular atrophy caused by aging, and accelerate wound healing after skin injury. For example, LL-37 induces endothelial cell proliferation, migration, and tubular formation through LPS and macrophage activation, increasing vascularization and re-epithelialization. AG-30 can induce the growth of endothelial cells and secrete angiogenic factors, which can reduce the decrease of blood vessels caused by aging so that the skin can obtain adequate nutrition. DRGN-1 can also be used to accelerate wound closure by cleaning the biofilm of infected bacteria and promoting keratinocyte migration and proliferation to form effective tissue regeneration without scars. CopA3 can inhibit the ability of dermal fibroblasts to secrete procollagen type Ⅰ caused by ultraviolet radiation and reduce skin aging. Therefore, antibacterial peptides play a role in the treatment of many skin diseases such as melanoma, acne, diabetic foot ulcer, and psoriasis, and can also be used as an additive for new skincare cosmetics.

Defects of antimicrobial peptides

  • High cost

Compared with the mature antibiotic synthesis industry, the production of antimicrobial peptides is basically in the laboratory stage, and there is no industrial concept or mature industrial system. Therefore, the synthetic cost of antimicrobial peptides is generally higher, which is 5~20 times that of conventional antibiotics.

  • Poor stability

antimicrobial peptides are more easily degraded by human protease affinity due to their special peptide or protein structure, and more easily inactivated under extreme pH or high-temperature environments. Therefore, the stability of most antimicrobial peptides is not good, and the effectiveness in vivo is difficult to maintain, which also leads to the efficacy of some antimicrobial peptides and the results of nanomedicine delivery application may be lower than expected.

  • Destroy cell structure

The positive charge in antimicrobial peptides can also interact with the negative ions on the surface of human or mammalian cell membranes, forming oligomers to destroy cell structure, leading to different degrees of hemolysis, apoptosis, mast cell degranulation, extracellular DNA transfer, and other adverse clinical phenomena.

Summary

Antimicrobial peptides may become a substitute for antibiotics in the future due to their unique antibacterial properties, broad-spectrum resistance to microorganisms (including drug-resistant bacteria), viruses, parasites, and other pathogens, and not easy to produce drug-resistant pathogenic microorganisms. At the same time, the powerful immunomodulatory and anticancer properties of antimicrobial peptides also increase the prospect of medical application. However, high cost, poor stability, biological toxicity, and other shortcomings also limit the development of antimicrobial peptides in clinical medicine. With the rapid development of new interdisciplinary disciplines such as synthetic biology and artificial intelligence, it is possible to provide a new technical platform for the design and synthesis of antimicrobial peptides and promote the transformation and application of antimicrobial peptides in different aspects and perspectives.

Reference

  1. WEI Daixu, GONG Hailun, ZHANG Xuwei. Biosynthesis of antimicrobial peptides and its medical application[J]. Synthetic Biology Journal20223(4): 709-727

 

Login

Welcome to WriteUpCafe Community

Join our community to engage with fellow bloggers and increase the visibility of your blog.
Join WriteUpCafe