Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Jun 1.
Published in final edited form as: J Appl Microbiol. 2016 Feb 12;120(6):1449–1465. doi: 10.1111/jam.13033

Biomedical Applications of Nisin

Jae M Shin 1,3, Ji Won Gwak 1, Pachiyappan Kamarajan 1, J Christopher Fenno 2, Alexander H Rickard 3, Yvonne L Kapila 1
PMCID: PMC4866897  NIHMSID: NIHMS746268  PMID: 26678028

Abstract

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 an FDA approved and GRAS (generally regarded as 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 defense peptides, nisin may activate the adaptive immune response and have an immunomodulatory role. Increasing evidence indicates that nisin can influence the growth of tumors 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.

Keywords: Nisin, Lantibiotic, Antimicrobial peptide, Infectious Disease, Oral Disease, Cancer, Biofilm

Nisin: A Bacterially-Derived Antimicrobial

Nisin is an antimicrobial peptide produced by certain Gram-positive bacteria that include Lactococcus and Streptococcus species (Lubelski et al., 2008; de Arauz et al., 2009). Nisin was first identified in 1928 in fermented milk cultures and commercially marketed in England in 1953 as an antimicrobial agent (Rogers and Whittier, 1928; Delves-Broughton et al., 1996). In 1969, nisin was approved by the Joint Food and Agriculture Organization/World Health Organization (FAO/WHO) as a safe food additive. Currently, nisin is licensed in over 50 countries, and it has made a significant impact in the food industry as a natural biopreservative for different types of foods (de Arauz et al., 2009). In the United States (US), nisin was approved by the Food and Drug Administration in 1988 and was given a generally regarded as safe (GRAS) designation for use in processed cheeses (Cotter et al., 2005).

The originally described variant of nisin, known as nisin A, is composed of 34 amino acids and is produced by Lactococcus lactis (Gross and Morell, 1971). Nisin belongs to a group of cationic peptide antimicrobials collectively called Type A (I) lantibiotics (Smith and Hillman, 2008). Nisin and other lantibiotics have gained considerable attention due to their potent and broad spectrum activity, low likelihood of promoting the development of bacterial resistance, and low cellular cytotoxicity at antimicrobial concentrations (Asaduzzaman and Sonomoto, 2009; Van Heel et al., 2011; Cotter et al., 2013; Shin et al., 2015). Similar to other lantibiotics, nisin contains several unusual amino acids as a result of enzymatic post-translational modifications (Sahl et al., 1995). Nisin contains dehydrated amino acid residues (serine and threonine) and thioether amino acids that form five lanthionine rings, which are characteristic of nisin and lantibiotics (Karakas et al., 1999; Wiedemann et al., 2001). As a food biopreservative, nisin serves as a broad-spectrum bacteriocin against mostly Gram-positive foodborne bacteria (Delves-Broughton et al., 1996; Severina et al., 1998; Cleveland et al., 2001). However, research has now shown that the antimicrobial action of nisin can extend to a range of non-food related bacteria (Blay et al., 2007; Shin et al., 2015). Studies have demonstrated that purified nisin and nisin in combination with other antibiotics can be effective against Gram-negative pathogens and that certain bioengineered nisin variants can enhance the activity against both Gram-positive and Gram-negative pathogens (Kuwano et al., 2005; Naghmouchi et al., 2010; Field et al., 2012). In addition, with recent improvements in biotechnology, researchers from interdisciplinary fields have bioengineered newer forms of nisin variants that have therapeutic potential for human diseases (Piper et al., 2011; Field et al., 2012; Rouse et al., 2012; Balciunas et al., 2013; Field et al., 2015).

Since its discovery, nisin has garnered significant influence in the food industry as an alternative biopreservative. However, with demonstrated safety over the past 40 years, the use of nisin has begun to expand to include a diverse array of unrelated applications, such as those related to the biomedical industry (Fig. 1). Many lantibiotics (and more broadly, other bacteriocins) have been reported to possess additional biological activities beyond their antimicrobial activities (Asaduzzaman and Sonomoto, 2009; Benmechernene et al., 2013; Kamarajan et al., 2015). For example, nisin has beneficial properties in the context of biomedical applications, including bacterial infections, cancer, oral diseases and more. This review will provide a comprehensive overview of the latest findings by focusing on the advances in nisin bioengineering and the new discoveries in biomedical applications of nisin.

Figure 1. Timeline of Nisin Development.

Figure 1

Open in a new tab

Natural and Bioengineered Variants of Nisin

Several other naturally-occurring variants of nisin have been reported. These variants have been identified from a range of taxonomically distinct organisms isolated from a broad range of environments. Nisin A was first discovered in L. lactis, an organism that is commonly found in dairy products and is the most widely studied nisin variant (Fig. 2) (Gross and Morell, 1971). Nisin Z, the closest variant of nisin A, was isolated from L. lactis NIZO22186 (Mulders et al., 1991). Nisin Z differs from nisin A by a single amino acid residue at position 27, asparagine instead of histidine (Fig. 2; Table 1) (Mulders et al., 1991). Nisin A and Z share similar properties as antimicrobials, but nisin Z has a superior rate of diffusion and solubility under neutral pH conditions (De Vos et al., 1993). Nisin F was isolated from L. lactis F10 in the feces of a freshwater catfish in South Africa and differs from nisin A by two amino acid residues (De Kwaadsteniet et al., 2008). Nisin F has two amino acid substitutions at position 27 and 30 (Fig. 2; Table 1). Nisin Q was isolated from L. lactis 61-14 that was cultured from a river in Japan (Zendo et al., 2003). Nisin Q contains four substitutions at position 15, 21, 27 and 30 (Fig. 2; Table 1). Nisin A, Z, F and Q have antimicrobial activity against a range of Staphylococcus aureus targets (Piper et al., 2011). Nisin U and U2 are more distantly related variants that were isolated from Streptococcus uberis, an organism that commonly inhabits the lips, skin, and udder tissues of cows and is found in raw milk (Wirawan et al., 2006). Nisin U and U2 contain nine and ten amino acid substitutions respectively, compared to nisin A (Table 1). Recently, nisin H was isolated from a Streptococcus hyointestinalis strain derived from porcine intestine (O'Connor et al., 2015). The amino acid sequence of nisin H has similarities to nisin peptides produced by both lactococcal and streptococcal strains (Table 1). Nisin H maintains the terminal amino acids found in nisin A, Z, F, and Q, while harnessing features of nisin U and U2, including a dehydroaminobutyric acid substitution at position 18 (Table 1). Furthermore, nisin P was identified by genome mining techniques in Streptococcus gallolyticus subsp. pasteurianus, an organism found in the alimentary tract of ruminants (Zhang et al., 2012). The protein sequence of nisin P closely resembles that of nisin U2 but differs from it by two substitutions at position 20 and 21 (Fig. 2; Table 1). Thus far, based on published reports, there are at least eight nisin variants that have been isolated, identified and sequenced for cross-analysis.

Figure 2. Peptide Structure of Nisin.

Figure 2

Open in a new tab

Modified amino acids are colored gray with black letters. Dha, dehydroalanine (from Alanine); Dhb, dehydrobutyrine (from Threonine); Ala-S-Ala, lanthionine; Abu-S-Ala; β-methyllanthionine. The hinge region is composed of Asparagine-Methionine-Lysine. Arrows indicate the sites of amino acid substitutions for natural variants.

Table 1. Natural and Bioengineered variants of nisin.

Amino acids in blue letters indicate the flexible hinge region. Yellow highlights indicate amino acid substitutions compared to nisin A. Please note that this table does not contain all variants that have been reported to date.

Natural Variants Unmodified Amino Acid Sequences Origin
Nisin A ITSISLCTPGCKTGALMGCNMKTATCHCSIHVSK Lactococcus lactis strains
(Gross et al., 1971)
Nisin Z ITSISLCTPGCKTGALMGCNMKTATCNCSIHVSK Lactococcus lactis NIZO 22186
(Mulders et al., 1991)
Nisin F ITSISLCTPGCKTGALMGCNMKTATCNCSVHVSK Lactococcus lactis subsp. lactis F10
(de Kwaadsteniet et al., 2008)
Nisin Q ITSISLCTPGCKTGVLMGCNLKTATCNCSVHVSK Lactococcus lactis 61-14
(Zendo et al., 2003)
Nisin H FTSISMCTPGCKTGALMTCNYKTATCHCSIKVSK Streptococcus hyointestinalis
(O'Connor et al., 2015)
Nisin U ITSKSLCTPGCKTGILMT CPLKTATCGCHFG Streptococcus uberis
(Wirawan et al., 2006)
Nisin U2 VTSKSLCTPGCKTGILMT CPLKTATCGCHFG Streptococcus uberis
(Wirawan et al., 2006)
Nisin P VTSKSLCTPGCKTGILMT CAIKTATCGCHFG Streptococcus galloyticus subsp. pasteurianus
(Zhang et al., 2012)
Bioengineered Variants
Nisin A S29A ITSISLCTPGCKTGALMGCNMKTATCHCAIHVSK L. lactis NZ9800
(Field et al., 2012)
Nisin A S29D ITSISLCTPGCKTGALMGCNMKTATCHCDIHVSK L. lactis NZ9800
(Field et al., 2012)
Nisin A S29E ITSISLCTPGCKTGALMGCNMKTATCHCEIHVSK L. lactis NZ9800
(Field et al., 2012)
Nisin A S29G ITSISLCTPGCKTGALMGCNMKTATCHCGIHVSK L. lactis NZ9800
(Field et al., 2008)
Nisin A K22T ITSISLCTPGCKTGALMGCNMTTATCHCSIHVSK L. lactis NZ9800
(Field et al., 2008)
Nisin A N20P ITSISLCTPGCKTGALMGCPMKTATCHCSIHVSK L. lactis NZ9800
(Field et al., 2008)
Nisin A M21V ITSISLCTPGCKTGALMGCNVKTATCHCSIHVSK L. lactis NZ9800
(Field et al., 2008)
Nisin A K22S ITSISLCTPGCKTGALMGCNMSTATCHCSIHVSK L. lactis NZ9800
(Field et al., 2008)
Nisin Z N20K ITSISLCTPGCKTGALMGCKMKTATCNCSIHVSK L. lactis NZ9800
(Yuan et al., 2004)
Nisin Z M21K ITSISLCTPGCKTGALMGCNKKTATCNCSIHVSK L. lactis NZ9800
(Yuan et al., 2004)
Open in a new tab

The potential for utilizing genetic tools to modify the activity of bacteriocins has been recognized for several decades (Gillor et al., 2005). In addition to the naturally occurring nisin variants, there are bioengineered forms of nisin that have been developed in attempts to enhance the efficacy and stability of nisin under different physiologic conditions, and to enhance its pharmacokinetic properties for a variety of biological applications (Field et al., 2015). Here, we describe several bioengineered nisin variants that have been recently identified. Nisin Z N20K and M21K were derived from the genetic modification of L. lactis NZ9800 and first reported by Yuan and colleagues. These genetically modified nisin variants exhibited enhanced activity against pathogenic Gram-negative bacteria, such as Shigella, Pseudomonas and Salmonella species (Yuan et al., 2004). Nisin Z N20K and M21K contain substitutions in the flexible hinge-region of the peptide backbone structure of nisin Z (Table 1). Furthermore, these variants displayed greater thermal stability at higher temperatures and solubility at neutral or alkaline pH (Yuan et al., 2004). The hinge region of nisin, which consists of three amino acids, asparagine-methionine-lysine, is located between the first three and the last two lanthionine-constricted rings of nisin. Modifications in the hinge region have been studied extensively because this region is important for the insertion of nisin into the bacterial membrane (Hasper et al., 2004; Lubelski et al., 2009; Ross and Vederas, 2011). Healy and coworkers demonstrated that mutants of the hinge region exhibited enhanced activity against specific indicator strains such as L. lactis HP, Streptococcus agalactiae ATCC 13813, Mycobacterium smegmatis MC2155 and S. aureus RF122 (Healy et al., 2013). In addition, Zhou and colleagues demonstrated that by altering the length of the hinge region of nisin, the efficacy of nisin against a panel of test microorganisms can be altered in a temperature and matrix dependent manner (Zhou et al., 2015). Recently, a wide range of bioengineered nisin peptides with greater activity and enhanced therapeutic properties against foodborne and clinical pathogens began surfacing in the literature. The newly bioengineered variants include nisin A K22T, A N20P, A M21V, A K22S, S29A, S29D, S29E and S29G (Table 1) (Field et al., 2008; Field et al., 2012). Field and colleagues applied site-directed and site-saturation mutagenesis to the hinge region residues of nisin A to successfully identify variants that displayed enhanced bioactivity and specificity against a range of Gram-positive drug-resistant, clinical veterinary and food-borne pathogens (Field et al., 2012). Thus, based on emerging reports, bioengineered variants of nisin appear to be promising candidates for future applications in health care.

Nisin and Treatment of Infectious Diseases

Certain human infectious diseases, such as antibiotic-resistant skin and soft tissue infections and especially biofilm-associated infections can be difficult to prevent and/or treat (Mah and O'Toole, 2001; Gilbert et al., 2002; Fauci and Morens, 2012). While conventional medical treatments that are based on antibiotics and antivirals have been used for bacterial and viral infections, the emergence of drug resistance has led to the search for alternative or adjunctive methods to treat these drug resistant diseases (Zetola et al., 2005). With decades of safe usage in the food industry, investigators have started exploring nisin as a potential alternative agent for infectious diseases, including drug-resistant infections, thereby also decreasing the use of antibiotics (Table 2) (Balciunas et al., 2013).

Table 2. Overview of Biomedical Applications of Nisin.

Disease Nisin Model Results References
Infections associated with drug resistant pathogens
Nisin A
(2.5% w/w purity)		 In vitro Nisin exhibited bactericidal effect against a large panel of Gram-positive bacteria including MRSA, S. pneumoniae and enterococci Severina et al., 1998
Nisaplin
(2.5% w/w purity)		 In vitro Nisin exhibited bactericidal effects against clinical isolates of S. pneumoniae, including penicillin- and other drug-resistant strains Goldstein et al., 1998
Nisin A
(> 95% purity)		 In vitro Nisin was active and highly bactericidal against C. difficile. Nisin was not absorbed by the gastrointestinal tract and did not have indiscriminate activity against all bowel flora or all anaerobes Bartoloni et al., 2004
Nisin A
(2.5% w/w purity)		 In vitro Nisin was active against drug resistant S. aureus Piper et al., 2009
Nisin A
(2.5% w/w purity)		 In vitro Nisin exhibited bactericidal effect against both MSSA and MRSA strains. In addition, it enhanced the activity of ciprofloxacin and vancomycin when used in combination Dosler et al., 2011
Nisin A
(2.5% w/w purity)		 In vitro Nisin exhibited bactericidal activity against both MRSA and other staphylococcal biofilms grown on medical devices Okuda et al., 2013
Nisaplin
(2.5% w/w purity)		 In vitro Nisin incorporated with 2,3-dihydroxybenzoic acid in nanofibers inhibited formation of MRSA biofilms Ahire and Dicks, 2015
Gastrointestinal Infections
Nisin A
(> 95% purity)		 In vitro Nisin did not disrupt the intestinal epithelial integrity, suggesting that it may be suitable for the treatment of gastrointestinal tract infections Maher and McClean, 2006
Nisin A and Z
(> 95% purity)		 In vitro Nisin A and Z exhibited similar inhibition effect against a broad range of intestinal Gram-positive bacteria Blay et al., 2007
Nisaplin
(2.5% w/w purity)		 In vitro Nisin was tableted with a pectin/HPMC mixture to form an enzymatically controlled delivery system for potential colonic drug delivery Ugurlu et al., 2007
Nisin Z In vitro and Mice Nisin producing strain L. lactis modulated the intestinal microbiota and reduced the intestinal colonization of vancomycin-resistant enterococci in infected mice. Millette et al., 2008
Nisin A and Z
(unknown purity)		 Ex vivo using jejunal chyme from fistulated dogs Nisin was insensitive to degradation by the components of the jejunal chyme Reunanen and Saris, 2009
Nisin F(Purity in arbitrary units) In vitro and Mice Nisin may have a stabilizing effect on the bacterial population of the gastro intestinal tract van Staden et al., 2011
Respiratory Infections
Nisin F
(Purity in arbitrary units)		 In vitro and Rats Nisin was used to control intranasal S. aureus infection De Kwaadsteniet et al., 2009
Nisaplin
(2.5% w/w purity)		 In vitro and Mice Low blood and tissue levels of nisin were sufficient to prevent the death of mice infected with S. pneumoniae Goldstein et al., 1998
Skin and Soft Tissue Infections
Nisaplin
(2.5% w/w purity)		 In vitro and Mice Nisin-containing nanofiber wound dressings significantly reduced S. aureus induced skin infections Heunis et al., 2013
Mastitis
Nisin Z
(18000 IU/mg)		 Cows Intramammary administration of nisin was effective in the treatment of mastitis in lactating dairy cows Cao et al., 2007
Wu et al., 2007
Nisin A
(Approximately 6 μg/ml)		 In vitro and Human Topical treatment of nisin was effective in the treatment of staphylococcal mastitis Fermandez et al., 2008
Cancer
Nisin A
(2.5% w/w purity)		 In vitro and Mice Nisin reduced HNSCC tumorigenesis by inducing preferential apoptosis, cell cycle arrest, and reducing cell proliferation in HNSCC cells Joo et al., 2012
Nisin A
(2.5% w/w purity)		 In vitro and Mice Combination of nisin and doxorubicin decreased tumor severity in skin carcinogenesis Preet et al., 2015
Nisin AP and ZP
(* P stands for pure; 95% purity)		 In vitro and Mice Nisin promoted HNSCC cell apoptosis, suppression of HNSCC cell proliferation, inhibition of angiogenesis and cancer orasphere formation. Nisin inhibited tumorigenesis and prolonged survival of mice Kamarajan et al., 2015
Nisin AP and ZP
(* P stands for pure; 95% purity)		 In vitro Nisin synergizes with cisplatin to induce apoptosis in HNSCC cells that are highly resistant to ionizing radiation and cisplatin Global Medical Discovery, 2015
Oral Health
Nisaplin
(2.5% w/w purity)		 Monkeys Nisin reduced the numbers of streptococci in the dental plaque of monkeys that received nisin in their foods Johnson et al., 1978
Nisin (Ambicin N)
(unknown purity)		 Dogs Nisin based mouthrinse prevented plaque build-up and gingival inflammation in beagle dogs Howell et al., 1993
Nisin A
(2.5% w/w purity)		 Ex vivo using the root canals of human teeth Nisin eradicated the colonization of E. faecalis Turner et al., 2004
Nisin Z
(unknown purity)		 In vitro Nisin significantly reduced the growth and transition of C. albicans Le Lay et al., 2008
Nisin Z
(unknown purity)		 In vitro Nisin may work synergistically with oral gingival cells to provide greater resistance against C. albicans infections Akerey et al., 2009
Nisin A
(2.5% w/w purity)		 In vitro Nisin inhibited the growth of cariogenic bacteria, including S. mutans Tong et al., 2010
Nisin A
(2.5% w/w purity)		 In vitro Nisin in combination with poly-lysine and sodium fluoride displayed synergistic effects in inhibiting planktonic and biofilm forms of S. mutans Najjar et al., 2009; Tong et al., 2011
Nisin A
(2.5% w/w purity)		 In vitro Nisin paired with MTAD improved post-antibiotic sub-MIC effects of MTAD against E. faecalis Tong et al., 2014
Nisin ZP
(* P stands for pure; 95% purity)		 In vitro Nisin inhibited growth of Gram-positive and Gram-negative oral pathogens and saliva derived multi-species biofilms without cytotoxicity to human oral cells Shin et al., 2015
Open in a new tab

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE) have become major medical problems in hospitals around the world. The difficulty in treating these infections has been extensively documented (Huycke et al., 1998; Chambers, 2001; Köck et al., 2010; Ahire and Dicks, 2015). MRSA and VRE are leading causes of bacterial nosocomial infections, urinary tract infections, and are known to be resistant to many standard therapies. For example, MRSA infections account for up to 70% of the S. aureus infections in intensive care units (Sahm et al., 1999; Diekema et al., 2001). Both MRSA and VRE infections can manifest as skin infections and in medical settings as bacteremias, pneumonia, and post-surgical infections (Huycke et al., 1998; Center for Disease Control and Prevention, MRSA Infections, 2015). Numerous studies have been published regarding the efficacy of nisin as an antimicrobial therapeutic (Piper et al., 2009; Dosler and Gerceker, 2011; Okuda et al., 2013; Singh et al., 2013; Ahire and Dicks, 2015). Piper and coworkers reported that nisin was especially effective against antibiotic resistant staphylococci, and that further research into nisin and other lantibiotic compounds could result in promising antimicrobial alternatives (Piper et al., 2009). Dosler and colleagues investigated the in vitro effects of nisin against MRSA strains, and concluded that nisin was a good candidate for further research by itself or in combination with conventional antibiotics, such as vancomycin or ciprofloxacin (Dosler and Gerceker, 2011). Other studies have shown that nisin in combination with conventional antibiotics can promote synergistic effects (Brumfitt et al., 2002; Singh et al., 2013). An earlier study by Severina and colleagues demonstrated that nisin exhibited bactericidal effects against a large panel of Gram-positive bacteria, including MRSA, VRE and S. pneumoniae (Severina et al., 1998). In addition, a nisin producing L. lactis strain was shown to reduce the intestinal colonization of VRE in a mouse infection model (Millette et al., 2008).

Bacteria that adhere to implanted medical devices or damaged tissue can form a biofilm and cause chronic infection (Stewart and Costerton, 2001). Biofilms are surface associated communities of microorganism that can be up to 1,000-times more resistant to antimicrobials. Treatment of these biofilms accounts for over a billion dollars in healthcare costs each year in the US (Mah and O'Toole, 2001; Gilbert et al., 2002). Okuda and colleagues investigated the antibiofilm effects of nisin against MRSA biofilms on medical devices and reported that nisin A compared to two other bacteriocins (lacticin Q and nukacin ISK-1) was most effective in the prevention of biofilm formation (Okuda et al., 2013). Recently, Ahire and Dicks demonstrated that a combination therapy of 2,3-dihydroxybenzoic acid, an antibiotic extracted from Flacourtia inermis fruit, and nisin resulted in an increase in iron concentrations that reduced biofilm formation of the MRSA Xen 31 strain (Ahire and Dicks, 2015).

The potential for using nisin to treat local site-specific infections has also been explored. For example, the antimicrobial effects of nisin against mastitis, respiratory, gastrointestinal, and skin infections has been reported (Table 2). In respiratory tract infections, although viral etiologies are common, these can progress to bacterial infections that further compromise the health status (Hament et al., 1999). The upper and lower respiratory tract is primarily infected by S. aureus (Micek et al., 2007; Weber et al., 2007; Bosch et al., 2013). De Kwaadsteniet and colleagues reported that nisin F safely inhibited the growth of S. aureus in the respiratory tract of immunocompromised rats (De Kwaadsteniet et al., 2009). Furthermore, studies have shown that nisin can exert synergistic effects when combined with lysozyme and lactoferrin, which are both antimicrobial proteins and normally secreted in the human respiratory tract (Nattress et al., 2001; Murdock et al., 2007; De Kwaadsteniet et al., 2009). It was proposed that while nisin deters cell growth by binding to the lipid II precursor of the cell wall, lysozyme and lactoferrin can further damage the glycosidic bonds in the peptidoglycan wall, and sequester iron necessary for cellular respiration, respectively (Arnold and Cole, 1977; Ganz, 2004; De Kwaadsteniet et al., 2009).

Superficial and invasive skin and soft tissue infections are commonly caused by S. aureus (Fridkin et al., 2005; Daum, 2007). MRSA skin infections are relatively uneventful but failure to treat effectively can result in death (Dakota, 1999). Heunis and coworkers investigated the efficacy of nisin using an electrospun nanofiber wound dressing containing nisin, which diffused active nisin onto skin wounds (Heunis et al., 2013). In a murine excisional skin infection model, the nisin-containing wound dressing significantly reduced the S. aureus colonization as analyzed by bioluminescence. In addition, the wound showed signs of accelerated healing (Heunis et al., 2013). Mastitis is a common inflammatory disease in lactating women that causes breastfeeding cessation (Foxman et al., 2002). S. aureus and S. epidermidis are two common etiologic agents that cause mastitis-associated infections (Foxman et al., 2002). Considering the potent antimicrobial properties of nisin against staphylococcal strains, investigators have explored using nisin as a clinical therapeutic for mastitis. Cao and colleagues reported that a nisin-based formulation was effective in the treatment of clinical mastitis in lactating dairy cows caused by several different mastitis pathogens (Cao et al., 2007). In addition, Wu and coworkers demonstrated that nisin Z was effective in treatment of subclinical mastitis caused by multiple mastitis pathogens in lactating dairy cows (Wu et al., 2007). Recently, Fernandez and others reported that topical nisin treatment alleviated clinical signs of mastitis and significantly reduced the staphylococcal count in breast milk of nisin treated women (Fernandez et al., 2008). Overall, as an alternative to conventional antibiotics, the latest research suggests that nisin has potential as a therapeutic against certain infectious pathogens and disease conditions.

Nisin and Oral Health

The pervasiveness of oral diseases, such as caries and periodontal diseases, remains high in developed and developing countries (Marcenes et al., 2013). Oral diseases are considered a major public health burden due to their high prevalence and incidence (Petersen, 2003). Therefore, research on new strategies to prevent and treat oral diseases are a focus of industry and many academic, and government institutions (Centers for Disease Control and Prevention, Chronic Disease Prevention and Health Promotion, 2015). Oral biofilms, including dental plaque, play a key role in the etiology and the progression of biofilm-associated oral diseases (Marsh, 2010; Zijnge et al., 2010). Enhanced antimicrobial resistance is associated with the accumulation of pathogens that cause dental caries and periodontal disease (Marsh, 2003; Aas et al., 2005). Nisin's potential as an oral antimicrobial was first described by Johnson and colleagues, who demonstrated that there were fewer numbers of streptococci in the dental plaque of monkeys that received nisin in their foods (Johnson et al., 1978). Later, Howell and coworkers demonstrated that a nisin-based antimicrobial mouthrinse exhibited promising clinical results in prevention of plaque build-up and gingival inflammation in beagle dogs (Howell et al., 1993). Thus, the idea of using nisin to improve oral health has been around for some time.

Emerging evidence continues to support the antimicrobial properties of nisin against oral pathogenic bacteria relevant to caries and periodontal diseases. Tong and colleagues demonstrated that nisin A can inhibit the growth of cariogenic bacteria, including Streptococcus mutans (Tong et al., 2010). Scanning electron microscopy confirmed that nisin exerted bactericidal activity by forming small pores on the surface of cells (Tong et al., 2010). Furthermore, investigators have reported that nisin in combination with poly-lysine and sodium fluoride displayed synergistic properties in inhibiting planktonic and biofilm forms of S. mutans (Najjar et al., 2009; Tong et al., 2011). Nisin A has been shown to inhibit the growth of Gram-positive oral bacteria such as Streptococcus sanguinis, Streptococcus sobrinus and Streptococcus gordonii (Tong et al., 2010). In addition, Shin and coworkers demonstrated that high purity nisin Z can inhibit the growth of Gram-negative oral colonizing pathogens, including Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans and Treponema denticola (Shin et al., 2015). Shin and colleagues also reported that nisin exerted anti-biofilm effects on saliva derived multi-species biofilms without causing cytotoxicity to human oral cells (Fig. 3) (Shin et al., 2015). As a cationic bacteriocin, nisin's mode of action may include inhibition of coaggregation of oral colonizers. Indeed, cationic antimicrobials can selectively inhibit coaggregation interactions of oral biofilm species (Smith et al., 1991).

Figure 3. Nisin inhibits the formation of multi-species biofilms in a Bioflux controlled flow microfluidic model system.

Figure 3

Open in a new tab

Cell containing saliva was added, then fed filter sterilized cell free saliva for 20–22 h at 37°C with or without nisin. Confocal microscopy images are represented in the x–y plane. A green signal indicates viable live cells (Syto 9) and a red signal indicates damaged/dead cells (propidium iodide). These images were previously published (Shin et al., 2015).

In addition to dental caries and periodontal disease, nisin's potential application to other oral diseases has been explored. Investigators have reported that nisin can inhibit Enterococcus faecalis, which is an opportunistic Gram-positive pathogen frequently recovered from infected root canals of teeth (Stuart et al., 2006). In an ex vivo root canal system, nisin successfully eradicated the colonization of E. faecalis (Turner et al., 2004). Nisin, when paired with MTAD (a common intracanal irrigant, consisting of 3% doxycycline, 4.5% citric acid, and 0.5% polysorbate 80 detergent), improved the post-antibiotic sub-MIC effects of MTAD against E. faecalis, and made it less resistant to alkaline environments (Tong et al., 2014). Another potential oral application of nisin was demonstrated in the treatment of oral candidiasis. Candida albicans is one of the most prevalent pathogens that cause mucosal fungal infections (Pfaller et al., 2002; Trick et al., 2002). The invasion of candida species into oral epithelial cells is a signature of oropharyngeal candidiasis (Eversole et al., 1997; Drago et al., 2000; Farah et al., 2000). Le Lay and colleagues reported that nisin Z can significantly reduce the growth and transition of C. albicans (Le Lay et al., 2008). In addition, nisin Z has the potential to work synergistically with oral gingival cells to provide greater resistance against C. albicans infections (Akerey et al., 2009). Thus, with recent reports highlighting the therapeutic potential of nisin in oral diseases, future studies will be essential to further evaluate the potential clinical role of nisin.

Bacteriocins and Cancer: Nisin as a Cancer Therapeutic

The potential for using bacterially-derived compounds to control infectious disease also extends to controlling cancers (Frankel et al., 2002; Lundin and Checkoway, 2009; Nobili et al., 2009). For example, antimicrobial peptides have been indicated to exhibit cytotoxic effects on cancer cells and thus may have therapeutic potential (Meyer and Harder, 2007; Boohaker et al., 2012). Specifically, purified bacteriocins, including pyocin, colicin, pediocin, microcin, and nisin have shown inhibitory properties against neoplastic cell lines and in xenograft mouse models (Cornut et al., 2008; Lagos et al., 2009; Yates et al., 2012; Shaikh et al., 2012; Yang et al., 2014). This is relevant because current treatment strategies have yet to reduce cancer-related deaths below a half million per year in the USA alone (Centers for Disease Control and Prevention, Leading Causes of Death, 2015). Cancer is a complex disease characterized by the dysregulated growth of abnormal cells. Significant progress has been made in the treatment of cancers, however the majority of treatments involve surgery and chemo- and radiation therapy, which are detrimental to normal cells and tissues and cause further morbidity (Patel et al., 2014; DeSantis et al., 2014).

Recently, Joo and colleagues explored the cytotoxic and antitumor properties of nisin A and discovered that it blocks head and neck squamous cell carcinoma (HNSCC) tumorigenesis (Joo et al., 2012). Nisin mediated these effects by inducing preferential apoptosis, cell cycle arrest, and reducing cell proliferation in HNSCC cells compared to primary oral keratinocytes. Nisin also reduced HNSCC tumorigenesis in vivo in a mouse model (Joo et al., 2012). Mechanistically, nisin exerted these effects on HNSCC, in part, through cation transport regulator homolog 1 (CHAC1), a proapoptotic cation transport regulator and through a concomitant CHAC1-independent influx of extracellular calcium (Mungrue et al., 2009; Joo et al., 2012). Nisin can interact with the negatively charged phospholipid heads of the cell membrane, thereby mediating its reorganization and forming pores that allow an influx of ions (Giffard et al., 1996; Moll et al., 1997). Since HNSCC cells and primary oral keratinocytes differ in their lipid membrane composition and function, and response toward calcium fluxes, the ability of nisin to differentially alter the transmembrane potential and membrane composition of HNSCC cells may explain its predominant effects on these cells (Ponec et al., 1984; Ponec et al., 1987; Tertoolen et al., 1988; Eckert, 1989; Gasparoni et al., 2004; Tripathi et al., 2012). Indeed, recent reports support this premise as the basis for the nisin-mediated differential apoptotic cell death and reduced proliferation of HNSCC cells compared to primary keratinocytes (Schweizer, 2009).

Recently, Kamarajan and coworkers focused on investigating the translational potential of a high purity form of nisin Z for the treatment of HNSCC (Kamarajan et al., 2015). The data support the role of nisin as an alternative therapeutic for HNSCC, since nisin promoted HNSCC cell apoptosis, suppression of HNSCC cell proliferation, inhibition of angiogenesis, inhibition of HNSCC orasphere formation, inhibition of tumorigenesis in vivo, and it prolonged survival in vivo (Fig. 4) (Kamarajan et al., 2015). Considering that the FDA has approved 83.25 mg/kg in humans as the no-observed-effect-level (NOEL) for nisin (66.7 mg/kg was used in mice as a cancer therapeutic dose), this study demonstrated the promising potential for nisin as an anti-cancer agent. In addition, Preet and colleagues demonstrated that combining doxorubicin, a conventional cancer drug, with nisin can potentiate the effectiveness of the treatment in terms of decreasing tumor severity in skin carcinogenesis (Preet et al., 2015). Kamarajan and colleagues also showed that high purity forms of nisin A and Z synergize with cisplatin to induce apoptosis in HNSCC cells that are highly resistant to ionizing radiation and cisplatin (Global Medical Discovery, 2015). Therapeutic strategies for utilizing nisin alone or in combination with other conventional drugs to treat cancer are still at an early stage. However, the few studies that have been reported demonstrate the significant anti-cancer potential of using nisin as a promising alternative or adjunctive therapeutic. Furthermore, increasing evidence suggests an etiologic linkage between the microbiome and cancers (Wroblewski et al., 2010; Bultman, 2014). Recent studies indicate that certain bacteria (i.e. oral bacteria) may promote carcinogenesis in humans (Ahn et al., 2012; Michaud and Izard, 2014). In these scenarios, it is possible that nisin may have dual benefits by altering or disrupting the microbiome and inhibiting the growth of cancer cells. Thus, nisin may be a useful therapeutic since it exerts both antimicrobial/biofilm and anti-cancer properties.

Figure 4. Nisin Z inhibits orasphere formation in HNSCC cells.

Figure 4

Open in a new tab

Phase contrast images of oraspheres in HNSCC cells (UM-SCC-17B) cultured under suspension conditions and treated with control media or media containing nisin Z (100 to 800 μg/ml) for 36 h. These images were previously published (Kamarajan et al., 2015).

Immunomodulatory Role of Nisin

Host-defense peptides (HDPs) are ubiquitous in nature. HDPs are small amphiphilic cationic peptides, which play an essential role in the innate immune response (Sahl and Bierbaum, 2008). Almost all living organisms use antimicrobial peptides or HDPs as an innate defense mechanism. Interestingly, despite differences in size and native structure, HDPs and bacterially secreted bacteriocins share similar physicochemical properties (Hancock and Sahl, 2006). Nisin is both a cationic and amphiphilic peptide, and thereby mediates diverse effects on membrane processes similar to HDPs (Cotter et al., 2005). Pablo and colleagues demonstrated that short-term dietary administration of nisin (as Nisaplin, containing 2.5% nisin A, 77.5% NaCl and non-fat dried milk) resulted in an increase in CD4 and CD8 T-lymphocytes, while decreasing the B-lymphocyte levels (Pablo et al., 1999). In addition, prolonged administration of nisin resulted in a return to normal levels of both B- and T-lymphocytes (Pablo et al., 1999). This study provided the first evidence of nisin's influence on the immune system of mice. Recently, Begde and coworkers reported that nisin was able to activate neutrophils, and suggested that nisin may be influencing multiple subsets of host immune cells (Begde et al., 2011). Considering that nisin appears to behave similar to HDPs, it is possible that the immunomodulatory properties associated with HDPs may also apply to nisin (Kindrachuck et al., 2013). Bacteriocins were once thought to have a very limited role in disrupting bacterial membranes and exerting bactericidal activity. However, Kindrachuck and colleagues demonstrated that purified nisin Z was capable of modulating the innate immune response by inducing chemokine synthesis and suppressing LPS-induced pro-inflammatory cytokines in human peripheral blood mononuclear cells (Kindrachuck et al., 2013). Furthermore, nisin Z promoted immunomodulatory responses within both ex vivo and in vivo model systems (Kindrachuck et al., 2013). These reports underscore nisin's significant potential for use in a variety of human diseases that are mediated by the host immune response and pathogenic biofilms, like periodontal disease. Given that the periodontal lesion is characterized by an initial burst of neutrophils that is followed by a B- and T-cell mediated immune response in its later stages, nisin could play a significant therapeutic role in modifying both the immune and biofilm signature of this lesion (Page and Schroeder, 1976). The ability of nisin to alter the host immune response provides yet another opportunity for its potential use within health care settings. Since information regarding the role of nisin in modulating the host immune response is limited, this area merits further examination.

Resistance to Nisin

Bacteriocins have different modes of action when compared to antibiotics (Cleveland et al., 2001; Cotter et al., 2005). Specifically, lantibiotic bacteriocins, such as nisin, require a docking molecule (lipid II), through which they target cells by forming pores in the membrane. This depletes the transmembrane potential and/or the pH gradient and results in the leakage of cellular materials (Peschel and Sahl, 2006). Although in binding to lipid II nisin is similar to other antibiotics, such as vancomycin, nisin is unique in that it can span the entire membrane by using the pyrophosphate cage as the anchoring point (Hsu et al., 2004). Some evidence suggests that resistance against nisin can arise from mutations that induce changes in the membrane and cell wall composition (thickening of the cell wall to prevent the nisin binding to lipid II), reducing the acidity of the extracellular medium to stimulate the binding of nisin to the cell wall and induce its degradation, prevent the insertion of nisin into the membrane, and transport or extrude nisin out across the membrane (Mantovani and Russell, 2001; Kramer et al., 2006; Kramer et al., 2008). These changes may occur independently or together and have been described as physiological adaptations (Sun et al., 2009). The cellular mechanisms of resistance to nisin are, however, still not well understood. One key reason for this stems from the fact that only a few examples of nisin resistance have emerged and only under laboratory conditions.

Lipid II plays an essential role in bacterial cell wall biosynthesis and growth, and nisin initiates its mode of action by binding to lipid II with high affinity (Breukink et al., 1999; Wiedemann et al., 2001). Kramer and colleagues tested whether nisin resistance could result from differences in the lipid II levels of Gram-positive bacteria (Kramer et al., 2004). Those studies suggested that there was no direct role for lipid II in nisin resistance as there was no correlation with the amount of lipid II present and increase in resistance (Kramer et al., 2004). It was recently reported that lack of antibiotic resistance to a newly described antibiotic was due to its targeting the highly conserved lipid II component of bacteria; nisin may be working in the same way (Ling et al., 2015).

Nisinase is a dehydropeptide reductase that can inactivate nisin through an enzymatic reaction (de Freire Bastos et al., 2014; Draper et al., 2015). Nisinase activity has been detected in Lactobacillus plantarum, Streptococcus thermophilus, Clostridium botulinum, L. lactis subsp. cremoris, E. faecalis and S. aureus (Kooy, 1952; Carlson and Bauer, 1957; Alifax and Chevalier, 1962; Rayman et al., 1983). However, despite all of the reports suggesting the presence of nisinase in several different species, there has not been a conclusive study indicating the presence of nisinase in L. lactis (Pongtharangku and Demirci, 2007). In addition, Sun and coworkers reported that nisin resistance protein (NSR) is a nisin degrading protease that non-nisin producing bacteria can produce as a novel mechanism for nisin resistance (Sun et al., 2009). NSR was capable of proteolytically cleaving the C-terminal tail of nisin, thereby inactivating and reducing nisin's antimicrobial activity by a 100-fold (Sun et al., 2009).

Currently, the majority of studies on the mechanisms of nisin resistance have been focused on single foodborne pathogens, such as Listeria monocytogenes (Crandall and Montville, 1998). A number of mechanisms are now known to contribute to and affect nisin resistance, including environmental stress and specific genetic components (Mantovani and Russell, 2001; Gravesen et al., 2001; Thedieck et al., 2006; Begley et al., 2010). As the applications of nisin expand even further into the biomedical field, it will be critical to study and monitor the development of nisin resistance in pathogenic organisms and cells relevant to disease processes. Antibiotic resistance is not an uncommon phenomenon, however, bacteriocins such as nisin are distinctly different from conventional antibiotics in both their synthesis and mode of action (Cleveland et al., 2001). Thus, characterization of specific genetic or protein components that may contribute to nisin resistance will be important to better understand any potential resistance issues that may arise in clinical settings.

Concluding Remarks: Outlook

In recent years, nisin research has shown its potential use in a broad range of fields, including food biopreservation and biomedical applications. Among different classes of lantibiotics, nisin is the most well-known and best-studied lantibiotic (Benmechernene et al., 2013). Considering that variants of nisin are now available in high purity forms from numerous commercial vendors, it is projected that more studies on different applications of nisin will be published. In addition, the mode of action of nisin in the context of human systems and disease will be better understood for newer biomedical applications. Currently, antibiotic resistance is a major concern in the food and biomedical industries. Until now, nisin has shown promising laboratory and clinical results as a useful therapeutic agent. Furthermore, different variants and forms of nisin may be combined with conventional drug(s) to promote synergistic outcomes. Further validation of nisin's usefulness in biomedical fields will require in vivo studies to evaluate its efficacy. Although nisin has been associated with the development of minimal resistance, it will be critical to continue surveying for potential novel mechanisms of nisin resistance in vitro and in vivo. There is still much knowledge to be gained, however current findings support the incorporation of nisin and/or other bacteriocins into a variety of disease therapies.

Acknowledgments

The authors are grateful for the support provided by the University of Michigan School of Dentistry, Department of Periodontics and Oral Medicine and the School of Public Health of University of Michigan, Department of Epidemiology, Center for Molecular Clinical Epidemiology of Infectious Diseases.

Funding: This work was supported in part by an IADR/GlaxoSmithKline Innovation in Oral Care Award and an NIH T-32 Training Grant (5 T32 DE 7057-38).

Footnotes

Transparency Declarations: All authors declare no conflicts of interest

References

  1. Ahire J, Dicks L. Nisin incorporated with 2,3-dihydroxybenzoic acid in nanofibers inhibits biofilm formation by a methicillin-resistant strain of Staphylococcus aureus. Probiot Antimicrob Proteins. 2015;7(1):52–9. doi: 10.1007/s12602-014-9171-5. [DOI] [PubMed] [Google Scholar]
  2. Aas JA, Paster BJ, Stokes LN, et al. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005;43(11):5721–5732. doi: 10.1128/JCM.43.11.5721-5732.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ahn J, Chen CY, Hayes RB. Oral microbiome and oral and gastrointestinal cancer risk. CCC. 2012;23(3):399–404. doi: 10.1007/s10552-011-9892-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Akerey B, Le Lay C, Fliss I, et al. In vitro efficacy of nisin Z against Candida albicans adhesion and transition following contact with normal human gingival cells. J Appl Microbiol. 2009;107(4):1298–1307. doi: 10.1111/j.1365-2672.2009.04312.x. [DOI] [PubMed] [Google Scholar]
  5. Alifax R, Chevalier R. Study of the nisinase produced by Streptococcus thermophilus. J Dairy Res. 1962;29:233–240. [Google Scholar]
  6. Arnold RR, Cole MF. A bactericidal effect for human lactoferrin. Science. 1977;197(4300):263–265. doi: 10.1126/science.327545. [DOI] [PubMed] [Google Scholar]
  7. Asaduzzaman SM, Sonomoto K. Lantibiotics: diverse activities and unique modes of action. J Biosci Bioeng. 2009;107(5):475–487. doi: 10.1016/j.jbiosc.2009.01.003. [DOI] [PubMed] [Google Scholar]
  8. Balciunas EM, Martinez FAC, Todorov SD, et al. Novel biotechnological applications of bacteriocins: a review. Food Control. 2013;32(1):134–142. [Google Scholar]
  9. Begde D, Bundale S, Mashitha P, et al. Immunomodulatory efficacy of nisin - a bacterial lantibiotic peptide. J Pept Sci. 2011;17(6):438–444. doi: 10.1002/psc.1341. [DOI] [PubMed] [Google Scholar]
  10. Begley M, Cotter PD, Hill C, et al. Glutamate decarboxylase-mediated nisin resistance in Listeria monocytogenes. Appl Environ Microbiol. 2010;76(19):6541–6546. doi: 10.1128/AEM.00203-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Benmechernene Z, Fernandez-No I, Kihal M, et al. Recent patents on bacteriocins: food and biomedical applications. Recent Patents DNA Gene Seq. 2013;7(1):66–73. doi: 10.2174/1872215611307010010. [DOI] [PubMed] [Google Scholar]
  12. Blay G, Lacroix C, Zihler A, et al. In vitro inhibition activity of nisin A, nisin Z, pediocin PA-1 and antibiotics against common intestinal bacteria. Lett Appl Microbiol. 2007;45(3):252–7. doi: 10.1111/j.1472-765X.2007.02178.x. [DOI] [PubMed] [Google Scholar]
  13. Boohaker RW, Lee M, Vishnubhotla P, et al. The use of therapeutic peptides to target and to kill cancer cells. Curr Med Chem. 2012;19(22):3794–3804. doi: 10.2174/092986712801661004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bosch AA, Biesbroek G, Trzcinski K, et al. Viral and bacterial interactions in the upper respiratory tract. PLoS Pathog. 2013;9(1):e1003057. doi: 10.1371/journal.ppat.1003057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Breukink E, Wiedemann I, Van Kraaij C, et al. Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic. Science. 1999;286:2361–2364. doi: 10.1126/science.286.5448.2361. [DOI] [PubMed] [Google Scholar]
  16. Brumfitt W, Salton MR, Hamilton-Miller JM. Nisin, alone and combined with peptidoglycan-modulating antibiotics: activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. J Antimicrob Chemother. 2002;50(5):731–734. doi: 10.1093/jac/dkf190. [DOI] [PubMed] [Google Scholar]
  17. Bultman SJ. Emerging roles of the microbiome in cancer. Carcinogenesis. 2014;35(2):249–255. doi: 10.1093/carcin/bgt392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Cao LT, Wu JQ, Xie F, et al. Efficacy of nisin in treatment of clinical mastitis in lactating dairy cows. J Dairy Sci. 2007;90(8):3980–3985. doi: 10.3168/jds.2007-0153. [DOI] [PubMed] [Google Scholar]
  19. Carlson S, Bauer H. A study of problems associated with resistance to nisin. Arch Hyg Bakteriol. 1957;141:445–460. [PubMed] [Google Scholar]
  20. Center for Disease Control and Prevention, Methicillin-resistant Staphylococcus Aureus (MRSA) [September 29, 2015];Infections. 2015 Available at: http://www.cdc.gov/mrsa/
  21. Center for Disease Control and Prevention. [September 29, 2015];Chronic Disease Prevention and Health Promotion. 2015 Available at: http://www.cdc.gov/chronicdisease/
  22. Centers for Disease Control and Prevention. [September 29, 2015];Leading Causes of Death. 2015 Available at: http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm.
  23. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001;7(2):178. doi: 10.3201/eid0702.010204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Cleveland J, Montville TJ, Nes IF, et al. Bacteriocins: safe, natural antimicrobials for food preservation. Int J Food Microbiol. 2001;71(1):1–20. doi: 10.1016/s0168-1605(01)00560-8. [DOI] [PubMed] [Google Scholar]
  25. Cornut G, Fortin C, Soulières D. Antineoplastic properties of bacteriocins: revisiting potential active agents. Am J Clin Oncol. 2008;31(4):399–404. doi: 10.1097/COC.0b013e31815e456d. [DOI] [PubMed] [Google Scholar]
  26. Cotter PD, Hill C, Ross RP. Bacteriocins: developing innate immunity for food. Nat Rev Microbiol. 2005;3(10):777–788. doi: 10.1038/nrmicro1273. [DOI] [PubMed] [Google Scholar]
  27. Cotter PD, Ross RP, Hill C. Bacteriocins - a viable alternative to antibiotics? Nat Rev Microbiol. 2013;11(2):95–105. doi: 10.1038/nrmicro2937. [DOI] [PubMed] [Google Scholar]
  28. Crandall AD, Montville TJ. Nisin resistance in Listeria monocytogenes ATCC 700302 is a complex phenotype. Appl Environ Microbiol. 1998;64(1):231–237. doi: 10.1128/aem.64.1.231-237.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Dakota N. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus - Minnesota and North Dakota, 1997-1999. Arch Dermatol. 1999;135(12):1566–1568. [Google Scholar]
  30. Daum RS. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. N Eng J Med. 2007;357(4):380–390. doi: 10.1056/NEJMcp070747. [DOI] [PubMed] [Google Scholar]
  31. De Arauz LJ, Jozala AF, Mazszola PG, et al. Nisin biotechnological production and application: a review. Trends Food Sci Tech. 2009;20(3):146–154. [Google Scholar]
  32. De Freire Bastos M, Coelho M, da Silva Santos O. Resistance to bacteriocins produced by Gram-positive bacteria. Microbiology. 2014;161:683–700. doi: 10.1099/mic.0.082289-0. [DOI] [PubMed] [Google Scholar]
  33. De Kwaadsteniet M, Doeschate KT, Dicks LMT, et al. Nisin F in the treatment of respiratory tract infections caused by Staphylococcus aureus. Lett Appl Microbiol. 2009;48(1):65–70. doi: 10.1111/j.1472-765X.2008.02488.x. [DOI] [PubMed] [Google Scholar]
  34. De Kwaadsteniet M, Ten Doeschate K, Dicks LMT. Characterization of the structural gene encoding nisin F, a new lantibiotic produced by a Lactococcus lactis subsp. lactis isolate from freshwater catfish (Clarias gariepinus) Appl Environ Microbiol. 2008;74(2):547–549. doi: 10.1128/AEM.01862-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. De Vos WM, Mulders JW, Siezen RJ, et al. Properties of nisin Z and distribution of its gene, nisZ, in Lactococcus lactis. Appl Environ Microbiol. 1993;59(1):213–218. doi: 10.1128/aem.59.1.213-218.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Delves-Broughton J, Blackburn P, Evans R, et al. Applications of the bacteriocin, nisin. Antonie van Leeuwenhoek. 1996;69(2):193–202. doi: 10.1007/BF00399424. [DOI] [PubMed] [Google Scholar]
  37. DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA: Cancer J Clin. 2014;64(4):252–271. doi: 10.3322/caac.21235. [DOI] [PubMed] [Google Scholar]
  38. Diekema DJ, Pfaller MA, Schmitz FJ, et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis. 2001;32(2):S114–S132. doi: 10.1086/320184. [DOI] [PubMed] [Google Scholar]
  39. Dosler S, Gerceker AA. In vitro activities of nisin alone or in combination with vancomycin and ciprofloxacin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains. Chemotherapy. 2011;57(6):511–516. doi: 10.1159/000335598. [DOI] [PubMed] [Google Scholar]
  40. Drago L, Mombelli B, De Vecchi E, et al. Candida albicans cellular internalization: a new pathogenic factor? Int J Antimicrob Agents. 2004;16(4):545–547. doi: 10.1016/s0924-8579(00)00296-x. [DOI] [PubMed] [Google Scholar]
  41. Draper LA, Cotter PD, Hill C, et al. Lantibiotic Resistance. Microbiol Mol Biol Rev. 2015;79(2):171–191. doi: 10.1128/MMBR.00051-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Eckert RL. Structure, function, and differentiation of the keratinocyte. Physiol Rev. 1989;69(4):1316–1346. doi: 10.1152/physrev.1989.69.4.1316. [DOI] [PubMed] [Google Scholar]
  43. Eversole LR, Reichart PA, Ficarra G, et al. Oral keratinocyte immune responses in HIV-associated candidiasis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84(4):372–380. doi: 10.1016/s1079-2104(97)90035-4. [DOI] [PubMed] [Google Scholar]
  44. Farah CS, Ashman RB, Challacombe SJ. Oral candidosis. Clin Dermatol. 2000;18(5):553–562. doi: 10.1016/s0738-081x(00)00145-0. [DOI] [PubMed] [Google Scholar]
  45. Fauci AS, Morens DM. The perpetual challenge of infectious diseases. N Eng J Med. 2012;366(5):454–461. doi: 10.1056/NEJMra1108296. [DOI] [PubMed] [Google Scholar]
  46. Fernández L, Delgado S, Herrero H, et al. The bacteriocin nisin, an effective agent for the treatment of staphylococcal mastitis during lactation. J Hum Lact. 2008;24(3):311–316. doi: 10.1177/0890334408317435. [DOI] [PubMed] [Google Scholar]
  47. Field D, Begley M, O'Connor PM, et al. Bioengineered nisin A derivatives with enhanced activity against both Gram-positive and Gram-negative pathogens. PLoS One. 2012;7(10):e46884. doi: 10.1371/journal.pone.0046884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Field D, Connor PM, Cotter PD, et al. The generation of nisin variants with enhanced activity against specific Gram-positive pathogens. Mol Microbiol. 2008;69(1):218–230. doi: 10.1111/j.1365-2958.2008.06279.x. [DOI] [PubMed] [Google Scholar]
  49. Field D, Cotter PD, Ross RP, et al. Bioengineering of the model lantibiotic nisin. Bioengineered. 2015;6(4):187–92. doi: 10.1080/21655979.2015.1049781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Foxman B, D'Arcy H, Gillespie B, et al. Lactation mastitis: occurrence and medical management among 946 breastfeeding women in the United States. Am J Epidemiol. 2002;155:103–14. doi: 10.1093/aje/155.2.103. [DOI] [PubMed] [Google Scholar]
  51. Frankel AE, Powell BL, Duesbery NS, et al. Anthrax fusion protein therapy of cancer. Curr Protein Pept Sci. 2002;3(4):399–407. doi: 10.2174/1389203023380567. [DOI] [PubMed] [Google Scholar]
  52. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Eng J Med. 2005;352(14):1436–1444. doi: 10.1056/NEJMoa043252. [DOI] [PubMed] [Google Scholar]
  53. Ganz T. Antimicrobial polypeptides. J Leukoc Biol. 2004;75(1):34–38. doi: 10.1189/jlb.0403150. [DOI] [PubMed] [Google Scholar]
  54. Gasparoni A, Fonzi L, Schneider GB, et al. Comparison of differentiation markers between normal and two squamous cell carcinoma cell lines in culture. Arch Oral Biol. 2004;49(8):653–664. doi: 10.1016/j.archoralbio.2004.02.010. [DOI] [PubMed] [Google Scholar]
  55. Giffard CJ, Ladha S, Mackie AR, et al. Interaction of nisin with planar lipid bilayers monitored by fluorescence recovery after photobleaching. J Membr Biol. 1996;151(3):293–300. doi: 10.1007/s002329900079. [DOI] [PubMed] [Google Scholar]
  56. Gilbert P, Maira-Litran T, McBain AJ, et al. The physiology and collective recalcitrance of microbial biofilm communities. Adv Microb Physiol. 2002;46:203–256. [PubMed] [Google Scholar]
  57. Gillor O, Nigro LM, Riley MA. Genetically engineered bacteriocins and their potential as the next generation of antimicrobials. Curr Pharm Des. 2005;11(8):1067–1075. doi: 10.2174/1381612053381666. [DOI] [PubMed] [Google Scholar]
  58. [November 12, 2015];Global Medical Discovery. 2015 Available at: https://globalmedicaldiscovery.com/key-drug-discovery-articles/nisin-synergizes-with-cisplatin-induce-apoptosis-in-hnscc-cells-highly-resistant-to-ionizing-radiation-cisplatin/
  59. Goldstein BP, Wei J, Greenberg K, et al. Activity of nisin against Streptococcus pneumoniae, in vitro, and in a mouse infection model. J Antimicrob Chemother. 1998;42:277–8. [PubMed] [Google Scholar]
  60. Gravesen A, Sørensen K, Aarestrup FM, et al. Spontaneous nisin-resistant Listeria monocytogenes mutants with increased expression of a putative penicillin-binding protein and their sensitivity to various antibiotics. Microb Drug Resist. 2001;7(2):127–135. doi: 10.1089/10766290152045002. [DOI] [PubMed] [Google Scholar]
  61. Gross E, Morell JL. Structure of nisin. J Am Chem Soc. 1971;93(18):4634–4635. doi: 10.1021/ja00747a073. [DOI] [PubMed] [Google Scholar]
  62. Hament JM, Kimpen JL, Fleer A, et al. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immuno Med Microbiol. 1999;26(3-4):189–195. doi: 10.1111/j.1574-695X.1999.tb01389.x. [DOI] [PubMed] [Google Scholar]
  63. Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24(12):1551–1557. doi: 10.1038/nbt1267. [DOI] [PubMed] [Google Scholar]
  64. Hasper HE, de Kruijff B, Breukink E. Assembly and stability of nisin-lipid II pores. Biochemistry. 2004;43(36):11567–11575. doi: 10.1021/bi049476b. [DOI] [PubMed] [Google Scholar]
  65. Healy B, Field D, O'Connor PM, et al. Intensive mutagenesis of the nisin hinge leads to the rational design of enhanced derivatives. PLoS One. 2013;8(11):e79563. doi: 10.1371/journal.pone.0079563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Heunis TD, Smith C, Dicks LMT, et al. Evaluation of a nisin-eluting nanofiber scaffold to treat Staphylococcus aureus-induced skin infections in mice. Antimicrob Agents Chemother. 2013;57(8):3928–3935. doi: 10.1128/AAC.00622-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Howell TH, Fiorellini JP, Blackburn P, et al. The effect of a mouthrinse based on nisin, a bacteriocin, on developing plaque and gingivitis in beagle dogs. J Clin Periodontol. 1993;20(5):335–339. doi: 10.1111/j.1600-051x.1993.tb00369.x. [DOI] [PubMed] [Google Scholar]
  68. Hsu STD, Breukink E, Tischenko E, et al. The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat Struct Biol. 2004;11(10):963–967. doi: 10.1038/nsmb830. [DOI] [PubMed] [Google Scholar]
  69. Huycke MM, Sahm DF, Gilmore MS. Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerg Infect Dis. 1998;4(2):239. doi: 10.3201/eid0402.980211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Johnson IH, Hayday H, Colman G. The effects of nisin on the microbial flora of the dental plaque of monkeys (Macaca fascicularis) J Appl Bacteriol. 1978;45(1):99–109. doi: 10.1111/j.1365-2672.1978.tb04203.x. [DOI] [PubMed] [Google Scholar]
  71. Joo NE, Ritchie K, Kamarajan P, et al. Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1. Cancer Med. 2012;1(3):295–305. doi: 10.1002/cam4.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Kamarajan P, Hayami T, Matte B, et al. Nisin ZP, a bacteriocin and food preservative, inhibits head and neck cancer tumorigenesis and prolongs survival. PloS One. 2015;10(7):e0131008. doi: 10.1371/journal.pone.0131008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Karakas Sen A, Narbad A, Horn N, et al. Post-translational modification of nisin. Eur J Biochem. 1999;261(2):524–532. doi: 10.1046/j.1432-1327.1999.00303.x. [DOI] [PubMed] [Google Scholar]
  74. Kindrachuk J, Jenssen H, Elliott M, et al. Manipulation of innate immunity by a bacterial secreted peptide: lantibiotic nisin Z is selectively immunomodulatory. Innate immunity. 2013;19(3):315–327. doi: 10.1177/1753425912461456. [DOI] [PubMed] [Google Scholar]
  75. Köck R, Becker K, Cookson B, et al. Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. Eur Surveill. 2010;15(41):19688. doi: 10.2807/ese.15.41.19688-en. [DOI] [PubMed] [Google Scholar]
  76. Kooy JS. Strains of Lactobacillus plantarum which inhibit the activity of the antibiotics produced by Streptococcus lactis. Ned Melk Zuiveltijdschr. 1952;6:323–330. [Google Scholar]
  77. Kramer NE, Hasper HE, van den Bogaard PT, et al. Increased D-alanylation of lipoteichoic acid and a thickened septum are main determinants in the nisin resistance mechanism of Lactococcus lactis. Microbiol. 2008;154(6):1755–1762. doi: 10.1099/mic.0.2007/015412-0. [DOI] [PubMed] [Google Scholar]
  78. Kramer NE, Smid EJ, Kok J, et al. Resistance of Gram-positive bacteria to nisin is not determined by lipid II levels. FEMS Microbiol Lett. 2004;239(1):157–161. doi: 10.1016/j.femsle.2004.08.033. [DOI] [PubMed] [Google Scholar]
  79. Kramer NE, van Hijum SA, Knol J, et al. Transcriptome analysis reveals mechanisms by which Lactococcus lactis acquires nisin resistance. Antimicrob Agents Chemother. 2006;50(5):1753–1761. doi: 10.1128/AAC.50.5.1753-1761.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Kuwano K, Tanaka N, Shimizu T, et al. Dual antibacterial mechanisms of nisin Z against Gram-positive and Gram-negative bacteria. Int J Antimicrob Agents. 2005;26(5):396–402. doi: 10.1016/j.ijantimicag.2005.08.010. [DOI] [PubMed] [Google Scholar]
  81. Lagos R, Tello M, Mercado G, et al. Antibacterial and antitumorigenic properties of microcin E492, a pore-forming bacteriocin. Curr Pharm Biotechnol. 2009;10(1):74–85. doi: 10.2174/138920109787048643. [DOI] [PubMed] [Google Scholar]
  82. Le Lay C, Akerey B, Fliss I, et al. Nisin Z inhibits the growth of Candida albicans and its transition from blastospore to hyphal form. J Appl Microbiol. 2008;105(5):1630–1639. doi: 10.1111/j.1365-2672.2008.03908.x. [DOI] [PubMed] [Google Scholar]
  83. Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455–459. doi: 10.1038/nature14098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Lubelski J, Khusainov R, Kuipers OP. Directionality and coordination of dehydration and ring formation during biosynthesis of the lantibiotic nisin. J Biol Chem. 2009;284(38):25962–25972. doi: 10.1074/jbc.M109.026690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Lubelski J, Rink R, Khusainov R, et al. Biosynthesis, immunity, regulation, mode of action and engineering of the model lantibiotic nisin. Cell Mol Life Sci. 2008;65(3):455–476. doi: 10.1007/s00018-007-7171-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Lundin JI, Checkoway H. Endotoxin and cancer. Environ Health Perspect. 2009;117(9):1344–1350. doi: 10.1289/ehp.0800439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Mah TFC, O'Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34–39. doi: 10.1016/s0966-842x(00)01913-2. [DOI] [PubMed] [Google Scholar]
  88. Maher S, McClean S. Investigation of the cytotoxicity of eukaryotic and prokaryotic antimicrobial peptides in intestinal epithelial cells in vitro. Biochem Pharm. 2006;71(9):1289–1298. doi: 10.1016/j.bcp.2006.01.012. [DOI] [PubMed] [Google Scholar]
  89. Mantovani HC, Russell JB. Nisin resistance of Streptococcus bovis. Appl Environ Microbiol. 2001;67(2):808–813. doi: 10.1128/AEM.67.2.808-813.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Marcenes W, Kassebaum NJ, Bernabé E, et al. Global burden of oral conditions in 1990-2010 A systematic analysis. J Dent Res. 2013;92(7):592–597. doi: 10.1177/0022034513490168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology. 2003;149(2):279–294. doi: 10.1099/mic.0.26082-0. [DOI] [PubMed] [Google Scholar]
  92. Marsh PD. Controlling the oral biofilm with antimicrobials. J Dent. 2010;38:S11–S15. doi: 10.1016/S0300-5712(10)70005-1. [DOI] [PubMed] [Google Scholar]
  93. Meyer JE, Harder J. Antimicrobial peptides in oral cancer. Curr Pharm Des. 2007;13(30):3119–3130. doi: 10.2174/138161207782110372. [DOI] [PubMed] [Google Scholar]
  94. Micek ST, Kollef KE, Reichley RM, et al. Health care-associated pneumonia and community-acquired pneumonia: a single-center experience. Antimicrob Agents Chemother. 2007;51(10):3568–3573. doi: 10.1128/AAC.00851-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Michaud DS, Izard J. Microbiota, oral microbiome, and pancreatic cancer. Cancer J. 2014;20(3):203. doi: 10.1097/PPO.0000000000000046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Millette M, Cornut G, Dupont C, et al. Capacity of human nisin-and pediocin-producing lactic acid bacteria to reduce intestinal colonization by vancomycin-resistant enterococci. Appl Environ Microbiol. 2008;74(7):1997–2003. doi: 10.1128/AEM.02150-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Moll GN, Clark J, Chan WC, et al. Role of transmembrane pH gradient and membrane binding in nisin pore formation. J Bacteriol. 1997;179(1):135–140. doi: 10.1128/jb.179.1.135-140.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Mulders JW, Boerrigter IJ, Rollema HS, et al. Identification and characterization of the lantibiotic nisin Z, a natural nisin variant. Eur J Biochem. 1991;201(3):581–584. doi: 10.1111/j.1432-1033.1991.tb16317.x. [DOI] [PubMed] [Google Scholar]
  99. Mungrue IN, Pagnon J, Kohannim O, et al. CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 2009;182(1):466–476. doi: 10.4049/jimmunol.182.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Murdock CA, Cleveland J, Matthews KR, et al. The synergistic effect of nisin and lactoferrin on the inhibition of Listeria monocytogenes and Escherichia coli O157: H7. Lett Appl Microbiol. 2007;44(3):255–261. doi: 10.1111/j.1472-765X.2006.02076.x. [DOI] [PubMed] [Google Scholar]
  101. Naghmouchi K, Drider D, Baah J, et al. Nisin A and polymyxin B as synergistic inhibitors of Gram-positive and Gram-negative bacteria. Probiotics Antimicrob Proteins. 2010;2(2):98–103. doi: 10.1007/s12602-009-9033-8. [DOI] [PubMed] [Google Scholar]
  102. Najjar MB, Kashtanov D, Chikindas ML. Natural antimicrobials ε-poly-l-lysine and nisin A for control of oral microflora. Probiotics and Antimicrob Proteins. 2009;1(2):143–147. doi: 10.1007/s12602-009-9020-0. [DOI] [PubMed] [Google Scholar]
  103. Nattress FM, Yost CK, Baker LP. Evaluation of the ability of lysozyme and nisin to control meat spoilage bacteria. Int J Food Microbiol. 2001;70(1):111–119. doi: 10.1016/s0168-1605(01)00531-1. [DOI] [PubMed] [Google Scholar]
  104. Nobili S, Lippi D, Witort E, et al. Natural compounds for cancer treatment and prevention. Pharm Res. 2009;59(6):365–378. doi: 10.1016/j.phrs.2009.01.017. [DOI] [PubMed] [Google Scholar]
  105. O'Connor PM, O'Shea EF, Guinane CM, et al. Nisin H is a new nisin variant produced by the gut-derived strain Streptococcus hyointestinalis DPC6484. Appl Environ Microbiol. 2015;81(12):3953–3960. doi: 10.1128/AEM.00212-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Okuda K, Zendo T, Sugimoto S, et al. Effects of bacteriocins on methicillin-resistant Staphylococcus aureus biofilm. Antimicrob Agents Chemother. 2013;57(11):5572–9. doi: 10.1128/AAC.00888-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Pablo MA, Gaforio JJ, Gallego AM, et al. Evaluation of immunomodulatory effects of nisin-containing diets on mice. FEMS Immunol Med Microbiol. 1999;24(1):35–42. doi: 10.1111/j.1574-695X.1999.tb01262.x. [DOI] [PubMed] [Google Scholar]
  108. Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab Invest. 1976;34(3):235–249. [PubMed] [Google Scholar]
  109. Patel JD, Krilov L, Adams S, et al. Clinical cancer advances 2013: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2014;32(2):129–160. doi: 10.1200/JCO.2013.53.7076. [DOI] [PubMed] [Google Scholar]
  110. Peschel A, Sahl HG. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol. 2006;4(7):529–536. doi: 10.1038/nrmicro1441. [DOI] [PubMed] [Google Scholar]
  111. Petersen PE. The World Oral Health Report 2003: continuous improvement of oral health in the 21st century–the approach of the WHO Global Oral Health Programme. Community Dent Oral Epidemiol. 2003;31(s1):3–24. doi: 10.1046/j..2003.com122.x. [DOI] [PubMed] [Google Scholar]
  112. Pfaller MA, Diekema DJ, Jones RN, et al. Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000. J Clin Microbiol. 2002;40(3):852–856. doi: 10.1128/JCM.40.3.852-856.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Piper C, Draper L, Cotter P, et al. A comparison of the activities of lacticin 3147 and nisin against drug-resistant Staphylococcus aureus and Enterococcus species. J Antimicrob Chemother. 2009;64(3):546–51. doi: 10.1093/jac/dkp221. [DOI] [PubMed] [Google Scholar]
  114. Piper C, Hill C, Cotter PD, et al. Bioengineering of a nisin A producing Lactococcus lactis to create isogenic strains producing the natural variants Nisin F, Q and Z. Microb Biotechnol. 2011;4(3):375–382. doi: 10.1111/j.1751-7915.2010.00207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Ponec M, Havekes L, Kempenaar J, et al. Defective low-density lipoprotein metabolism in cultured, normal, transformed, and malignant keratinocytes. J Invest Dermatol. 1984;83(6):436–440. doi: 10.1111/1523-1747.ep12273538. [DOI] [PubMed] [Google Scholar]
  116. Ponec M, Kempenaar J, Boonstra J. Regulation of lipid synthesis in relation to keratinocyte differentiation capacity. Biochimica et Biophysica Acta. 1987;921(3):512–521. doi: 10.1016/0005-2760(87)90079-8. [DOI] [PubMed] [Google Scholar]
  117. Pongtharangku T, Demirci A. Online recovery of nisin during fermentation and its effect on nisin production in biofilm reactor. Appl Microbiol Biotechnol. 2007;74(3):555–562. doi: 10.1007/s00253-006-0697-7. [DOI] [PubMed] [Google Scholar]
  118. Preet S, Bharati S, Panjeta A, et al. Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis - a possible adjunct therapy. Tumor Biol. 2015:1–8. doi: 10.1007/s13277-015-3571-3. [DOI] [PubMed] [Google Scholar]
  119. Rayman K, Malik N, Hurst A. Failure of nisin to inhibit outgrowth of Clostridium botulinum in a model cured meat system. Appl Environ Microbiol. 1983;46:1450–1452. doi: 10.1128/aem.46.6.1450-1452.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Rogers LA, Whittier EO. Limiting factors in the lactic fermentation. J Bacteriol. 1928;16(4):211. doi: 10.1128/jb.16.4.211-229.1928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Ross AC, Vederas JC. Fundamental functionality: recent developments in understanding the structure-activity relationships of lantibiotic peptides. J Antibiot. 2011;64(1):27–34. doi: 10.1038/ja.2010.136. [DOI] [PubMed] [Google Scholar]
  122. Rouse S, Field D, Daly KM, et al. Bioengineered nisin derivatives with enhanced activity in complex matrices. Microb Biotechnol. 2012;5(4):501–508. doi: 10.1111/j.1751-7915.2011.00324.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Sahl HG, Bierbaum G. Multiple activities in natural antimicrobials-multiple activities of natural agents such as defensins and bacteriocins suggest a change in strategy when developing new antimicrobials. Microbe. 2008;3(10):467. [Google Scholar]
  124. Sahl HG, Jack RW, Bierbaum G. Biosynthesis and biological activities of lantibiotics with unique post-translational modifications. Eur J Biochem. 1995;230(3):827–853. doi: 10.1111/j.1432-1033.1995.tb20627.x. [DOI] [PubMed] [Google Scholar]
  125. Sahm DF, Marsilio MK, Piazza G. Antimicrobial resistance in key bloodstream bacterial isolates: electronic surveillance with the Surveillance Network Database - USA. Clin Infect Dis. 1999;29(2):259–263. doi: 10.1086/520195. [DOI] [PubMed] [Google Scholar]
  126. Schweizer F. Cationic amphiphilic peptides with cancer-selective toxicity. Eur J Pharm. 2009;625(1):190–194. doi: 10.1016/j.ejphar.2009.08.043. [DOI] [PubMed] [Google Scholar]
  127. Severina E, Severin A, Tomasz A. Antibacterial efficacy of nisin against multidrug-resistant Gram-positive pathogens. J Antimicrob Chemother. 1998;41(3):341–347. doi: 10.1093/jac/41.3.341. [DOI] [PubMed] [Google Scholar]
  128. Shaikh F, Abhinand PA, Ragunath PK. Identification & characterization of Lactobacillus salavarius bacteriocins and its relevance in cancer therapeutics. Bioinformation. 2012;8(13):589. doi: 10.6026/97320630008589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Shin JM, Ateia I, Paulus JR, et al. Antimicrobial nisin acts against saliva derived multi-species biofilms without cytotoxicity to human oral cells. Frontiers Microbiol. 2015;6:617. doi: 10.3389/fmicb.2015.00617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Singh AP, Prabha V, Rishi P. Value addition in the efficacy of conventional antibiotics by nisin against Salmonella. PLoS One. 2013;8(10):e76844. doi: 10.1371/journal.pone.0076844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Smith L, Hillman JD. Therapeutic potential of type A (I) lantibiotics, a group of cationic peptide antibiotics. Curr Opin Microbiol. 2008;11(5):401–408. doi: 10.1016/j.mib.2008.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Smith RN, Andersen RN, Kolenbrander PE. Inhibition of intergeneric coaggregation among oral bacteria by cetylpyridinium chloride, chlorhexidine digluconate and octenidine dihydrochloride. J Perio Res. 1991;26(5):422–428. doi: 10.1111/j.1600-0765.1991.tb01732.x. [DOI] [PubMed] [Google Scholar]
  133. Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet. 2001;358(9276):135–138. doi: 10.1016/s0140-6736(01)05321-1. [DOI] [PubMed] [Google Scholar]
  134. Stuart CH, Schwartz SA, Beeson TJ, et al. Enterococcus faecalis: its role in root canal treatment failure and current concepts in retreatment. J Endod. 2006;32(2):93–98. doi: 10.1016/j.joen.2005.10.049. [DOI] [PubMed] [Google Scholar]
  135. Sun Z, Zhong J, Liang X, et al. Novel mechanism for nisin resistance via proteolytic degradation of nisin by the nisin resistance protein NSR. Antimicrob Agents Chemother. 2009;53(5):1964–1973. doi: 10.1128/AAC.01382-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Tertoolen LG, Kempenaar J, Boonstra J, et al. Lateral mobility of plasma membrane lipids in normal and transformed keratinocytes. Biochem Biophys Res Commun. 1988;152(2):491–496. doi: 10.1016/s0006-291x(88)80064-0. [DOI] [PubMed] [Google Scholar]
  137. Thedieck K, Hain T, Mohamed W, et al. The MprF protein is required for lysinylation of phospholipids in listerial membranes and confers resistance to cationic antimicrobial peptides (CAMPs) on Listeria monocytogenes. Mol Microbiol. 2006;62(5):1325–1339. doi: 10.1111/j.1365-2958.2006.05452.x. [DOI] [PubMed] [Google Scholar]
  138. Tong Z, Dong L, Zhou L, et al. Nisin inhibits dental caries-associated microorganism in vitro. Peptides. 2010;31(11):2003–2008. doi: 10.1016/j.peptides.2010.07.016. [DOI] [PubMed] [Google Scholar]
  139. Tong Z, Zhang Y, Ling J, et al. An in vitro study on the effects of nisin on the antibacterial activities of 18 antibiotics against Enterococcus faecalis. PloS One. 2014;9(2) doi: 10.1371/journal.pone.0089209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  140. Tong Z, Zhou L, Li J, et al. In vitro evaluation of the antibacterial activities of MTAD in combination with nisin against Enterococcus faecalis. J Endod. 2011;37(8):1116–1120. doi: 10.1016/j.joen.2011.03.020. [DOI] [PubMed] [Google Scholar]
  141. Trick WE, Fridkin SK, Edwards JR, et al. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989 - 1999. Clin Infect Dis. 2002;35(5):627–630. doi: 10.1086/342300. [DOI] [PubMed] [Google Scholar]
  142. Tripathi P, Kamarajan P, Somashekar BS, et al. Delineating metabolic signatures of head and neck squamous cell carcinoma: Phospholipase A 2, a potential therapeutic target. Int J Biochem Cell Biol. 2012;44(11):1852–1861. doi: 10.1016/j.biocel.2012.06.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Turner SR, Love RM, Lyons KM. An in vitro investigation of the antibacterial effect of nisin in root canals and canal wall radicular dentine. I Endod J. 2004;37(10):664–671. doi: 10.1111/j.1365-2591.2004.00846.x. [DOI] [PubMed] [Google Scholar]
  144. Van Heel AJ, Montalban-Lopez M, Kuipers OP. Evaluating the feasibility of lantibiotics as an alternative therapy against bacterial infections in humans. Expert Opin Drug Metab Toxicol. 2011;7(6):675–680. doi: 10.1517/17425255.2011.573478. [DOI] [PubMed] [Google Scholar]
  145. Van Staden DA, Brand AM, Endo A, et al. Nisin F, intraperitoneally injected, may have a stabilizing effect on the bacterial population in the gastro-intestinal tract, as determined in a preliminary study with mice as model. Lett Appl Microbiol. 2011;53(2):198–201. doi: 10.1111/j.1472-765X.2011.03091.x. [DOI] [PubMed] [Google Scholar]
  146. Weber DJ, Rutala WA, Sickbert-Bennett EE, et al. Microbiology of ventilator–associated pneumonia compared with that of hospital-acquired pneumonia. Infect Control. 2007;28(07):825–831. doi: 10.1086/518460. [DOI] [PubMed] [Google Scholar]
  147. Wiedemann I, Breukink E, van Kraaij C, et al. Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J Biol Chem. 2001;276(3):1772–1779. doi: 10.1074/jbc.M006770200. [DOI] [PubMed] [Google Scholar]
  148. Wirawan RE, Klesse NA, Jack RW, et al. Molecular and genetic characterization of a novel nisin variant produced by Streptococcus uberis. Appl Environ Microbiol. 2006;72(2):1148–1156. doi: 10.1128/AEM.72.2.1148-1156.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Wroblewski LE, Peek RM, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23(4):713–739. doi: 10.1128/CMR.00011-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  150. Wu J, Hu S, Cao L. Therapeutic effect of nisin Z on subclinical mastitis in lactating cows. Antimicrob Agents Chemother. 2007;51(9):3131–3135. doi: 10.1128/AAC.00629-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. Yang SC, Lin CH, Sung CT, et al. Antibacterial activities of bacteriocins: application in foods and pharmaceuticals. Frontiers Microbiol. 2014;5:241. doi: 10.3389/fmicb.2014.00241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  152. Yates KR, Welsh J, Udegbunam NO, et al. Duramycin exhibits antiproliferative properties and induces apoptosis in tumour cells. Blood Coagul Fibrinolysis. 2012;23(5):396–401. doi: 10.1097/MBC.0b013e3283538875. [DOI] [PubMed] [Google Scholar]
  153. Yuan J, Zhang ZZ, Chen XZ, et al. Site-directed mutagenesis of the hinge region of nisin Z and properties of nisin Z mutants. Appl Microbiol Biotechnol. 2004;64(6):806–815. doi: 10.1007/s00253-004-1599-1. [DOI] [PubMed] [Google Scholar]
  154. Zendo T, Fukao M, Ueda K, et al. Identification of the lantibiotic nisin Q, a new natural nisin variant produced by Lactococcus lactis 61-14 isolated from a river in Japan. Biosci Biotechnol Biochem. 2003;67(7):1616–1619. doi: 10.1271/bbb.67.1616. [DOI] [PubMed] [Google Scholar]
  155. Zetola N, Francis JS, Nuermberger EL, et al. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis. 2005;5:275–286. doi: 10.1016/S1473-3099(05)70112-2. [DOI] [PubMed] [Google Scholar]
  156. Zhang Q, Yu Y, Vélasquez JE, et al. Evolution of lanthipeptide synthetases. Proc Natl Acad Sci USA. 2012;109(45):18361–18366. doi: 10.1073/pnas.1210393109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Zhou L, van Heel AJ, Kuipers OP. The length of a lantibiotic hinge region has profound influence on antimicrobial activity and host specificity. Frontiers Microbiol. 2015;6:11. doi: 10.3389/fmicb.2015.00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Zijnge V, van Leeuwen MBM, Degener JE, et al. Oral biofilm architecture on natural teeth. PLoS One. 2010;5:e9321. doi: 10.1371/journal.pone.0009321. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES