Biomedical applications of nisin Shin, J.M.; Gwak, J.W.; Kamarajan, P. ...
Journal of applied microbiology,
June 2016, Volume:
120, Issue:
6
Journal Article
Peer reviewed
Open access
Summary
Nisin is a bacteriocin produced by a group of Gram‐positive bacteria that belongs to Lactococcus and Streptococcus species. Nisin is classified as a Type A (I) lantibiotic that is synthesized ...from mRNA and the translated peptide contains several unusual amino acids due to post‐translational modifications. Over the past few decades, nisin has been used widely as a food biopreservative. Since then, many natural and genetically modified variants of nisin have been identified and studied for their unique antimicrobial properties. Nisin is FDA approved and generally regarded as a safe peptide with recognized potential for clinical use. Over the past two decades the application of nisin has been extended to biomedical fields. Studies have reported that nisin can prevent the growth of drug‐resistant bacterial strains, such as methicillin‐resistant Staphylococcus aureus, Streptococcus pneumoniae, Enterococci and Clostridium difficile. Nisin has now been shown to have antimicrobial activity against both Gram‐positive and Gram‐negative disease‐associated pathogens. Nisin has been reported to have anti‐biofilm properties and can work synergistically in combination with conventional therapeutic drugs. In addition, like host‐defence peptides, nisin may activate the adaptive immune response and have an immunomodulatory role. Increasing evidence indicates that nisin can influence the growth of tumours and exhibit selective cytotoxicity towards cancer cells. Collectively, the application of nisin has advanced beyond its role as a food biopreservative. Thus, this review will describe and compare studies on nisin and provide insight into its future biomedical applications.
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Antimicrobial peptides are evolving as novel therapeutic options against the increasing problem of multidrug-resistant microorganisms, and nisin is one such avenue. However, some bacteria possess a ...specific nisin resistance system (NSR), which cleaves the peptide reducing its bactericidal efficacy. NSR-based resistance was identified in strains of Streptococcus uberis, a ubiquitous pathogen that causes mastitis in dairy cattle. Previous studies have demonstrated that a nisin A derivative termed nisin PV, featuring S29P and I30V, exhibits enhanced resistance to proteolytic cleavage by NSR. Our objective was to investigate the ability of this nisin derivative to eradicate and inhibit biofilms of S. uberis DPC 5344 and
ATCC 700407 (
) using crystal violet (biomass), 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) (viability) assays, and confocal microscopy (viability and architecture). When preestablished biofilms were assessed, both peptides reduced biofilm biomass by over 60% compared to that of the untreated controls. However, a 42% higher reduction in viability was observed following treatment with nisin PV compared to that of nisin A. Accordingly, confocal microscopy analysis revealed significantly more dead cells on the biofilm upper surface and a reduced thickness following treatment with nisin PV. When biofilm inhibition was assessed, nisin PV inhibited biofilm formation and decreased viability up to 56% and 85% more than nisin A, respectively. Confocal microscopy analysis revealed a lack of biofilm for
ATCC 700407 and only dead cells for
DPC 5344. These results suggest that nisin PV is a promising alternative to effectively reduce the biofilm formation of
strains carrying NSR.
One of the four most prevalent species of bovine mastitis-causing pathogens is
Its ability to form biofilms confers on the bacteria greater resistance to antibiotics, requiring higher doses to be more effective. In a bid to limit antibiotic resistance development, the need for alternative antimicrobials is paramount. Bacteriocins such as nisin represent one such alternative that could alleviate the impact of mastitis caused by
However, many strains of
have been shown to possess nisin resistance determinants, such as the nisin resistance protein (NSR). In this study, we demonstrate the ability of nisin and a nisin derivative termed PV that is insensitive to NSR to prevent and remove biofilms of NSR-producing
strains. These findings will add new information to the antimicrobial bacteriocins and control of
research fields specifically in relation to biofilms and
mastitis-associated strains.
The skin microbiota is thought to play a key role in host protection from infection. Nisin J is a novel nisin variant produced by
APC 2923, a strain isolated from the toe web space area in a ...screening study performed on the human skin microbiota. Whole-genome sequencing and mass spectrometry of the purified peptide confirmed that
APC 2923 produces a 3,458-Da bacteriocin, designated nisin J, which exhibited antimicrobial activity against a range of Gram-positive pathogens, including methicillin-resistant
(MRSA) and
The gene order in the nisin J gene cluster (
) differs from that of other nisin variants in that it is lacking the nisin regulatory genes,
, as well as the nisin immunity gene
Nisin J has 9 amino acid changes compared to prototypical nisin A, with 8 amino acid substitutions, 6 of which are not present in other nisin variants (Ile4Lys, Met17Gln, Gly18Thr, Asn20Phe, Met21Ala, Ile30Gly, Val33His, and Lys34Thr), and an extra amino acid close to the C terminus, rendering nisin J the only nisin variant to contain 35 amino acids. This is the first report of a nisin variant produced by a
species and the first nisin producer isolated from human skin.
This study describes the characterization of nisin J, the first example of a natural nisin variant, produced by a human skin isolate of staphylococcal origin. Nisin J displays inhibitory activity against a wide range of bacterial targets, including MRSA. This work demonstrates the potential of human commensals as a source for novel antimicrobials that could form part of the solution to antibiotic resistance across a broad range of bacterial pathogens.
Summary
The emergence and dissemination of antibiotic resistant bacteria is a major medical challenge. Lantibiotics are highly modified bacterially produced antimicrobial peptides that have attracted ...considerable interest as alternatives or adjuncts to existing antibiotics. Nisin, the most widely studied and commercially exploited lantibiotic, exhibits high efficacy against many pathogens. However, some clinically relevant bacteria express highly specific membrane‐associated nisin resistance proteins. One notable example is the nisin resistance protein that acts by cleaving the peptide bond between ring E and the adjacent serine 29, resulting in a truncated peptide with significantly less activity. We utilised a complete bank of bioengineered nisin (nisin A) producers in which the serine 29 residue has been replaced with every alternative amino acid. The nisin A S29P derivative was found to be as active as nisin A against a variety of bacterial targets but, crucially, exhibited a 20‐fold increase in specific activity against a strain expressing the nisin resistance protein. Another derivative, nisin PV, exhibited similar properties but was much less prone to oxidation. This version of nisin with enhanced resistance to specific resistance mechanisms could prove useful in the fight against antibiotic resistant pathogens.
Here we report that a strategy involving molecular approaches (site‐specific and site‐saturation mutagenesis) of the nisA structural gene has generated fully active variants of nisin with enhanced resistance to the nisin resistance protein. The study demonstrates the potential of molecular bioengineering to overcome the issue of lantibiotic peptide vulnerability to proteolytic breakdown by replacing the residues that serve as recognition sites for dedicated resistance proteins.
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► Lantibiotics are produced by Gram-positive bacteria. ► The producer strains have developed an immunity system consisting of LanFEG and or LanI. ► The paradigm for lantibiotic biosynthesis, ...expression as well as immunity is nisin from L. lactis. ► The immunity genes LanFEG and LanI of L. lactis act against its own produced nisin, which is the focus of this review.
Lantibiotics are small peptides produced by Gram-positive bacteria, which are ribosomally synthesized as a prepeptide. Their genes are highly organized in operons containing all the genes required for maturation, transport, immunity and synthesis. The best-characterized lantibiotic is nisin from Lactococcus lactis. Nisin is active against other Gram-positive bacteria via various modes of actions. To prevent activity against its producer strain, an autoimmunity system has developed consisting of different proteins, the ABC transporter NisFEG and a membrane anchored protein NisI. Together, they circumvent the ability of nisin to fulfill its action and cause cell death of L. lactis. Within this review, the mechanism of regulation, biosynthesis and activity of the immunity machinery will be discussed. Furthermore a short description about the application of these immunity proteins in both medical and industrial fields is highlighted.
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The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes.
Treatment of subclinical mastitis (SCM) during ...lactation is rarely recommended due to concerns related to both antimicrobial usage and the costs associated with milk discard. Nisin is a naturally produced antimicrobial peptide with a gram-positive spectrum that, when given to dairy cows, does not require milk discard. We evaluated the economic impact of the treatment of SCM during early lactation using a nisin-based intramammary treatment under different scenarios that included various treatment costs, milk prices, and cure rates. We stochastically simulated the dynamics of SCM detected during the first week of lactation. The net economic impact was expressed in US dollars per case. The probabilities of an event and their related costs were estimated using a model that was based on pathogen-specific assumptions selected from peer-reviewed articles. Nisin cure rates were based on results of pivotal studies included in the US Food and Drug Administration (FDA) approval submission. Based on our model, the average cost of a case of intramammary infection (i.e., only true-positive cases) in early lactation was $170 (90% = $148–$187), whereas the cost of a clinical mastitis case was $521 (90% range = $435–$581). Both estimates varied with etiology, parity, and stage of lactation. When comparing the net cost of SCM cases (i.e., CMT-positive tests) detected during the first week of lactation, nisin treatment generated an average positive economic impact of $19 per CMT-positive case. The use of nisin to treat SCM was beneficial 93% of the time. Based on the sensitivity analysis, treatment would result in an economically beneficial outcome for 95% and 73% of multiparous and primiparous cows, respectively. At the herd level, use of intramammary nisin to treat SCM in cows in early lactation was economically beneficial in most tested scenarios. However, the economic impact was highly influenced by factors such as rate of bacteriological cure, cost of treatment, and parity of the affected animal. These factors should be considered when deciding to use nisin as a treatment for SCM.
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Nisin is a natural preservative for many food products. This bacteriocin is mainly used in dairy and meat products. Nisin inhibits pathogenic food borne bacteria such as Listeria monocytogenes and ...many other Gram-positive food spoilage microorganisms. Nisin can be used alone or in combination with other preservatives or also with several physical treatments. This paper reviews physicochemical and biological properties of nisin, the main factors affecting its antimicrobial effectiveness, and its food applications as an additive directly incorporated into food matrices.
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•The elasticity of the film was significantly improved by the incorporation of PVA.•WVP and OP were dependent on CS/PVA ratio.•Initial diffusion of Nisin could be well described by the Fickian ...equation.•pH, ionic strength, film composition and temperature affected Nisin diffusion.•Diffusion of Nisin from film was spontaneous and endothermic.
The aim of this study was to evaluate the kinetics and functional effectiveness of Nisin loaded chitosan/poly(vinyl alcohol) (Nisin–CS/PVA) as an antibacterial packaging film. The films were prepared by coating method and Staphylococcus aureus (S. aureus, ATCC6538) was used as test bacterium. The intermolecular hydrogen bonds between CS and PVA molecules were confirmed. The elasticity of films was significantly improved by the incorporation of PVA, and the film could also bear a relative high tensile strength at 26.7MPa for CS/PVA=1/1. As CS/PVA ratio decreased, the water vapor permeability (WVP) decreased and reached its minimum value 0.983×10−10gm−1s−1 at CS/PVA=1/1, meanwhile, oxygen permeability (OP) increased but still lower than 0.91cm3μmm−2d−1kPa−1 for CS/PVA=1/1 as the CS/PVA ratio was above 1:1. The initial diffusion of nisin (Mt/M∞<2/3) from CS/PVA film could be well described by the Fickian diffusion equation. Owing to the positively charged nisin at pH below isoelectric point (pI, 8.8) and its increasing dissolubility in water as the pH reduced, the diffusion of nisin from the films strongly depended on pH and ionic strength besides CS/PVA ratio and temperature. Moreover, the thermodynamic parameters suggested the spontaneous and endothermic diffusion of nisin from the films. The resulting data can provide some valuable information for the design of film in structure and ingredient.
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In this work, carbohydrate nanoparticles were created to prolong the efficacy of antimicrobial peptide against pathogens. Nisin and Listeria monocytogenes were used as the peptide and pathogen ...models, respectively, and phytoglycogen (PG)-based nanoparticles were developed as carriers of nisin. PG from su1 mutant maize was subjected to β-amylolysis as well as subsequent succinate or octenyl succinate substitutions. The goal was to minimize the loss of peptide during storage and meanwhile realize an effective release in the presence of bacteria. The capabilities of PG derivatives as carriers of nisin were evaluated using centrifugal ultrafiltration, zeta-potential, and the initial availability of nisin against L. monocytogenes. All methods indicated that nisin loading was favored by a high degree of substitution (DS), presence of hydrophobic octenyl moiety, and β-amylolysis of PG nanoparticles. To evaluate the prolonged nisin efficacy, preparations containing nisin and PG derivatives were loaded into a BHI-agar deep-well model (mimicking nisin depletion at the nutrient-containing surface). The residual inhibitory activities of preparations against L. monocytogenes were monitored during 21days of storage at 4°C. The results showed that all PG derivatives led to the prolonged retention of nisin activity and the longest retention was associated with high DS, β-amylolysis, and octenyl succinate. Evidently, both electrostatic and hydrophobic interactions are the driving forces of nisin adsorption, and the glucan structure at the nanoparticle surface also affects nisin loading and retention during storage.
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An antimicrobial peptide, nisin Z, was embedded within polyelectrolyte multilayers (PEMs) composed of natural polysaccharides in order to explore the potential of forming a multilayer with ...antimicrobial properties. Using attenuated total reflection Fourier transform infrared spectroscopy (ATR FTIR), the formation of carrageenan/chitosan multilayers and the inclusion of nisin Z in two different configurations was investigated. Approximately 0.89 µg cm
nisin Z was contained within a 4.5 bilayer film. The antimicrobial properties of these films were also investigated. The peptide containing films were able to kill over 90% and 99% of planktonic and biofilm cells, respectively, against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) strains compared to control films. Additionally, surface topography and wettability studies using atomic force microscopy (AFM) and the captive bubble technique revealed that surface roughness and hydrophobicity was similar for both nisin containing multilayers. This suggests that the antimicrobial efficacy of the peptide is unaffected by its location within the multilayer. Overall, these results demonstrate the potential to embed and protect natural antimicrobials within a multilayer to create functionalised coatings that may be desired by industry, such as in the food, biomaterials, and pharmaceutical industry sectors.
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