IngredientsPolylysine refers to several types of lysine homopolymers, which may differ from each other in terms of stereochemistry (D/L; the L form is natural and usually assumed) and link position (α/ε). Of these types, only ε-poly-L-lysine is produced naturally. The precursor amino acid lysine contains two amino groups, one at the α-carbon and one at the ε-carbon. Either can be the location of polymerization, resulting in α-polylysine or ε-polylysine. This article focuses primarily on ε-poly-L-lysine (ε-PL), the naturally occurring form used in food preservation and biomedical research.
The principal synonyms and designations for ε-poly-L-lysine include:
ε-Polylysine is a polymer made up of multiple lysine molecules linked together by ε-amide bonds. More specifically, ε-poly-L-lysine is a naturally produced, cationic homopolymer of 25–35 L-lysine units (as a result of Streptomyces albulus fermentation), connected by ε-amido bonds compounded by an ε-amino group of one L-lysine and an α-carboxyl group of another L-lysine. Polylysine is a homopolypeptide belonging to the group of cationic polymers: at pH 7, polylysine contains a positively charged hydrophilic amino group.
In contrast, α-polylysine is a synthetic polymer, which can be composed of either L-lysine or D-lysine. "L" and "D" refer to the chirality at lysine's central carbon. This results in poly-L-lysine (PLL) and poly-D-lysine (PDL) respectively. These synthetic forms are widely used in cell culture and laboratory research but are distinct from the naturally fermented ε-PL that is the focus of food and health applications.
ε-Polylysine molecular weight is between 3200–4500 g/mol (degree of polymerization = 25–35). ε-Polylysine is hygroscopic and a light yellow powder. It is soluble in water, slightly soluble in ethanol, and insoluble in organic solvents such as ethyl acetate and ether. Comprised of a straight-chain polymer of L-lysine, its potency remains unaffected by pH variations and it sustains stability even at high temperatures (120°C for 20 minutes), ensuring consistent performance.
Most commercially available high-concentration ε-polylysine powders are the hydrochloride type. ε-Polylysine hydrochloride cannot be said to be a pure natural material because the salt-forming reaction during its manufacturing process corresponds to a chemical synthesis process. Hydrochlorination makes ε-polylysine easier to powder. Most commercially available high-concentration ε-polylysine powder products are of the hydrochloride type.
ε-Polylysine is a food preservative manufactured from a fermentation process using Streptomyces albulus under aerobic conditions. ε-Poly-L-lysine (ε-PL) is a non-ribosomal polypeptide primarily biosynthesized by Streptomyces albulus, consisting of 25–35 lysine residues.
In 1977, ε-PL was accidentally discovered as an extracellular secretion produced by S. albulus NBRC14147. Following this discovery, no ε-PL-producing microbe was isolated until a dye-based method was developed in 2002. Using this method, a total of 10 ε-PL producers were isolated from 300 soil samples and were identified as members of the genera Streptomyces, Epichloë, Streptoverticillium, and Kitasatospora. ε-PL can be biosynthesized by Streptomycetaceae and ergot fungi.
ε-Poly-L-lysine (ε-PL) produced as a secondary metabolite of Streptomyces albulus has long been used as a natural food preservative in a number of countries, including Japan, the United States, South Korea, and China.
Free-form ε-polylysine is very difficult to powder due to its high hygroscopicity. Therefore, some manufacturers produce a 25% aqueous solution and a 50% powder which contains 50% dextrin as an excipient. 100% ε-polylysine free-form powder is difficult to produce industrially. Most powders with a concentration of 90% or more ε-polylysine are of the hydrochloride type.
Common preparations encountered in commerce include:
The production of ε-polylysine by natural fermentation was first described by researchers Shoji Shima and Heiichi Sakai in 1977. In 1977, Japanese scholars S. Shima and H. Sakai, in the process of screening Dragendorff-positive (DP) substances from microorganisms, discovered that a strain of actinomycete No. 346 could produce a large amount of stable DP substances. Analysis of the hydrolysate confirmed that the DP substance is a homopolymer of 25–30 lysine residues.
In 1977, Shima and Sakai isolated Streptomyces albulus NBRC14147 (formerly strain 346) from soil as a producer of ε-poly-L-lysine (ε-PL), which consists of 25 to 35 L-lysine residues with an isopeptide linkage between its ε-amino and α-carboxyl groups.
Since the late 1980s, ε-polylysine has been approved by the Japanese Ministry of Health, Labour and Welfare as a preservative in food. ε-PL has been a popular food preservative in Japan since the late 1980s, followed by Korea and China, and has been given Generally Recognized As Safe (GRAS) status in the USA.
ε-PL has no documented history of use in traditional or folk medicine systems predating its modern discovery. Unlike many plant-derived supplements with centuries of empirical use, ε-PL was identified exclusively through modern microbiological screening. Its first formally recorded use was as a food preservative in Japanese commercial products in the late 1980s following its characterization in the 1977–1984 research publications of Shima and Sakai.
From a scientific standpoint, ε-polylysine is a cationic poly(amino acid) made from lysine residues linked in a way that differs from ordinary dietary peptides. That unusual structure helps explain why it functions as an antimicrobial rather than just another amino-acid ingredient. The defining structural feature is that the peptide bonds are formed between the ε-amino group of one lysine and the α-carboxyl group of the adjacent residue, a configuration not found in ribosomal protein synthesis. This produces a polymer that is highly cationic at physiological pH.
ε-Polylysine is polymerized by 25–30 lysine groups, is relatively stable to pH and heat, and its antibacterial effect is related to the degree of polymerization and the environment. The molecular weight range of polylysine between 3600–4300 g/mol corresponds to the best antibacterial activity.
Epsilon-poly-L-lysine (ε-PL) is a natural antimicrobial cationic peptide which is generally regarded as safe (GRAS) as a food preservative. Although its antimicrobial activity is well documented, its mechanism of action has only been vaguely described in older literature.
Research published in Applied and Environmental Microbiology (2014) clarified the mechanism using Escherichia coli and Listeria innocua as model organisms:
A separate study examining activity against E. coli O157:H7 found:
The antimicrobial mechanism of ε-PL predominantly involves disrupting cell membrane integrity and inducing oxidative stress through reactive oxygen species (ROS) generation.
These results demonstrated that ε-PL showed its antibacterial activity by changing the integrity and permeability of cell membranes, leading to rapid cell death.
ε-PL is biodegradable, water-soluble, heat-stable and exhibits a widely antimicrobial spectrum, including yeast, fungi, Gram-positive and Gram-negative bacteria, as well as antiphage activity. The ε-PL has broad antimicrobial spectra against various Gram-positive and Gram-negative bacteria, fungi, yeasts, and specific viruses.
ε-Polylysine antibacterial activity may be reduced due to the binding with acidic polysaccharides, hydrochlorides, phosphates, copper ions, or others. ε-Polylysine antibacterial activity can be enhanced with hydrochloric acid, citric acid, malic acid, glycine, and higher fatty glycerides.
In one study, ε-PL inhibited human and porcine pancreatic lipase activity in substrate emulsions containing bile salts and phosphatidylcholine, in the concentration range of 10–1000 mg/L. At the same concentrations, it also destroyed the emulsifying activity, suggesting that lipase inhibitory activity and emulsion breakdown activity were associated.
ε-PL maintained its lipase inhibitory activity after incubation with trypsin, α-chymotrypsin, and pepsin, whereas α-PL did not. This resistance to proteolytic degradation in the gastrointestinal tract may be relevant to its potential metabolic effects.
Evidence level: Strong (multiple peer-reviewed studies; regulatory approval in several jurisdictions)
ε-PL can effectively inhibit the growth of Escherichia coli O157 and Listeria monocytogenes, thereby extending the shelf life of raw milk at low temperatures from 8 days to 16 days. Besides inhibiting the growth of various microorganisms, ε-PL also maintains the sensory quality and nutritional value of foods. For instance, adding ε-PL to fresh juices can significantly extend their shelf life and prevent microbial contamination.
In a study examining minimal inhibitory concentrations of ε-PL and citral against five E. coli O157:H7 strains, MICs were 2–4 μg/mL for ε-PL and 0.5–1 μg/mL for citral, with fractional inhibitory concentration indices of 0.25–0.375. The results of the time-kill assay revealed that a stronger bactericidal effect in laboratory medium might be exerted by the combination against E. coli O157:H7 than in a food model.
Li et al. (2017) found that an alginate-based edible coating containing 0.05% ε-PL significantly inhibited the growth of yeast and mold, while maintaining the green color, total chlorophyll content, and antioxidant capacity of fresh-cut kiwifruit.
The combination of ε-PL with other food additives can further improve the antimicrobial effect. Specifically, published research has demonstrated synergistic activity when ε-PL is combined with nisin against food-borne pathogens including Bacillus cereus and Listeria monocytogenes.
In research on phytopathogenic bacteria, the minimum inhibitory concentration (MIC) of ε-PL ranged from 80 μg/mL for Xanthomonas citri to 600 μg/mL for Ralstonia solanacearum and Xanthomonas euvesicatoria.
Evidence level: Preliminary (mostly in vitro and early-stage research; no completed human clinical trials specifically for antiviral indications)
In the biomedical industry, ε-PL was originally used as an effective antitumor and antiviral adjuvant for introducing high levels of serum interferon in monkeys, chimpanzees, and humans.
Polylysines possess a high positive charge with a linear polymeric structure and have earlier been reported to inhibit replication of HIV-1 and influenza A viruses. A study published in Nanoscale investigated the antiviral activity of hyperbranched polylysine nanopolymers (HPNs) against SARS-CoV-2. The results showed that HPNs exhibited antiviral activity with a 50% inhibitory concentration (IC50) value of 125 μg/mL. Upon examination of cell morphologies, it was found that HPNs had a protective effect against cytopathic damage at twice the IC50 concentration when shown to restore the cell monolayer of Vero E6 cells. These findings are preclinical only, and no human trials have evaluated polylysine for viral infections.
Evidence level: Preliminary (in vitro and early animal data; no clinical trials in humans)
A study on ε-PL and citral found that the compounds alone or in combination exhibited potential 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, and the expression of superoxide dismutase 1 and glutathione peroxidase 1 protein increased. The preliminary antitumor activity effect of the combination was better than ε-PL or citral alone. These findings indicated that the combination of ε-PL and citral could not only be used as a promising naturally sourced food preservative but also potentially in the pharmaceutical industry.
Although the main use of ε-PL is as a food preservative, ε-PL and ε-PL-based polymers have shown potential in biomedical fields. The antitumor evidence as of current literature is confined to in vitro experiments and animal model studies; no controlled human clinical trials have been conducted for oncological indications.
Evidence level: Preliminary animal data only; no human clinical evidence available in the literature
A study published in The Journal of Nutrition (2003) reported that: The plasma triacylglycerol concentration in rats intragastrically administered ≥15 mg/kg of both fat emulsion and ε-PL was significantly lower at 2 and 3 h after administration than that in rats administered fat emulsion alone (P < 0.05). These results strongly suggest that ε-PL is able to suppress dietary fat absorption from the small intestine by inhibiting pancreatic lipase activity.
Oral administration of ε-polylysine to rats reduced the peak plasma triacylglycerol concentration. In vitro, ε-polylysine and polylysine strongly inhibited the hydrolysis by either pancreatic lipase or carboxylester lipase.
It must be emphasized that all lipase-inhibitory and anti-obesity effects have been demonstrated only in rat studies. No human clinical trials have examined whether ε-PL affects body weight, fat absorption, or lipid parameters in people.
Evidence level: Experimental and preclinical; no approved human therapeutic products based on ε-PL as of the available literature
Recent studies have shown that ε-PL can serve as an effective drug carrier due to its high biocompatibility in target cells, high drug loading capacity, wide range of molecular sizes appropriate for specific needs, as well as non-toxicity and excellent biodegradability in target cells.
Besides its use in the food industry, ε-PL has numerous applications in the pharmaceutical industry as drug carriers, nanoparticles, gene carriers, liposomes, interferon inducers, lipase inhibitors, hydrogels, and coating materials.
Many recent applications of ε-PL in the biomedicine industry, such as dressing material and suture, depend on its antimicrobial capacity. Additionally, ε-PL has been used in bio-based wood preservation, antimicrobial therapeutics, fibrous membrane wound dressings, and nanotechnology.
Based on the peer-reviewed literature, ε-PL has been studied in relation to the following biological systems and health areas:
ε-Polylysine is food grade and meets FAO/WHO specifications. It is certified as GRAS (Generally Recognized As Safe) by the US FDA with US GRAS No. GRN000135.
In 2004, FDA had no questions regarding the conclusion of Japanese manufacturer Chisso Corporation that polylysine was generally recognized as safe (GRAS) for use as an antimicrobial agent in cooked rice or sushi rice at the maximum use level of 50 mg/kg. In 2011, FDA also had no questions regarding the conclusion of the supplier Purac Biochem b.v. that polylysine was GRAS under the intended uses as an antimicrobial agent in several food categories except for meat and poultry products at levels up to 0.025%.
ε-PL has been widely used as a natural food preservative in many countries, including Japan, Korea, and the United States as well as China.
Reported use levels in studies and regulatory filings include:
ε-Polylysine was practically non-toxic in an acute oral toxicity study in rats, with no mortality up to 5 g/kg and was not mutagenic in bacterial reversion assays.
Absorption, distribution, metabolism, and excretion (ADME) studies on 14C-radiolabeled ε-polylysine, given in a single dose to fasted male rats at 100 mg/kg, revealed low absorption from the gastrointestinal tract.
ε-Polylysine has been the subject of feeding studies of subchronic and chronic duration in rats using relatively high maximum concentrations in the diet of 50,000 and 20,000 ppm respectively. Even at these concentrations, neither study produced any toxicologically significant adverse effect in the animals; a transient weight reduction was associated with poor diet palatability because of the bitterness of the test material.
Mouse-feeding experiments verified that the polymer has almost no acute or chronic toxicity.
A series of pharmacokinetic and metabolic profile studies on ε-polylysine have been conducted in rats in order to provide a better understanding of the reason for its lack of toxicological effects in subchronic and chronic feeding bioassays using relatively high concentrations in the diet up to 50,000 ppm. The low gastrointestinal absorption demonstrated in the ADME studies — using radiolabeled material at 100 mg/kg in fasted rats — is considered a key factor in explaining its safety at effective food-preservation concentrations. The compound is metabolized to its constituent amino acid L-lysine, which is an essential dietary nutrient.
ε-Polylysine antibacterial activity may be reduced due to binding with acidic polysaccharides, hydrochlorides, phosphates, copper ions, or other compounds. In food formulation contexts, the interaction of ε-PL with negatively charged macromolecules (such as proteins and polysaccharides) can reduce its effective concentration. This is relevant to both efficacy in complex food matrices and to the theoretical systemic availability of orally ingested ε-PL.
ε-Polylysine did not have a significant impact on lipid digestion in one in vitro study. However, it did form strong electrostatic complexes with mixed micelles, which could decrease the transport and absorption of lipids in the small intestine. These results have important implications for the incorporation of polylysine into food systems, particularly those containing lipophilic nutrients.
Although naturally occurring ε-PL has a bitter flavor, ε-PL is widely used as a food preservative to improve the quality and shelf life of numerous foods, including starch-based foods, seafood, dairy products, as well as fruits and vegetables. The bitterness of ε-PL at higher concentrations is the principal organoleptic concern noted in safety feeding studies, where it was associated with transient reduced feed intake in animals.
α-Polylysine is a synthetic polymer, which can be composed of either L-lysine or D-lysine. The synthetic poly-L-lysine (PLL) and poly-D-lysine (PDL) used as laboratory reagents (e.g., for cell culture coating surfaces) have a different regulatory and toxicological profile than naturally fermented ε-PL. Laboratory-grade α-PLL is not an approved food ingredient and its safety profile in humans is not established for oral consumption. The GRAS designation and the ADME safety data discussed throughout this article apply specifically to naturally fermented ε-poly-L-lysine.
The combination of ε-PL with other food additives can further improve the antimicrobial effect. ε-PL acts synergistically with nisin, organic acids (citric acid, malic acid), glycine, and ethanol. While this enhances its utility as a food preservative, the combination of ε-PL with anionic food components can reduce its antimicrobial potency. No documented adverse drug–drug interactions in a clinical pharmacological sense have been reported in the peer-reviewed literature, consistent with the finding that systemic absorption from oral ingestion is low.
The following points characterize the current state of evidence and its limitations:
Health conditions that Polylysine may help support.
Body systems that Polylysine may help support.
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