Lantibiotic Nisin

Nisin is a peptide-based antibiotic from the lantibiotic (lanthioninc-containing antibiotic) family [2]. It is produced by certain strains of Lactococcus lactis and is active 

The structural formulas of lanthionine, 3-methyllanthionine, dehydroalanine, and (Z)-dehydrobutyrine are also shown. 

The chemical structure of lipid II is shown, and the binding sites of vancomycin and nisin are indicated. 

In 1960, Ramseier [22] discovered that nisin causes leakage of intracellular molecules from cells. Later, it was shown that it disturbs the membrane potential and interferes with energy transdudion [23]. In addition, it causes inhibition of biosynthesis of the cell wall processes by blocking the synthesis of peptidoglycans [24] and by binding to the precursor lipid II [25]. However, micromolar amounts of nisin are needed to permeate artificial membranes [26,27] or to inhibit cell wall synthesis in vitro [28], while the in vivo activity of nisin is in the nanomolar range. As vancomycin, which binds to the peptide motif in lipid II, inhibited the antibacterial activity and 

Other lantibiotics that do not have the ability to form pores and indeed do not cause cell leakage have nevertheless still an impressive antibacterial effect in vivo. With respect to this, an alternative mechanism of antibacterial activity was recently described by which members of the lantibiotic family kill Gram-positive bacteria by binding lipid II and removing it from the cell division site (or septum) and thus block cell wall synthesis [35]. 

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Notwithstanding the aforementioned difficulty in detecting specific target proteins other than the types normally observed in the taxonomic fingerprints from whole bacteria MALDI spectra (i.e., ribosomal proteins), some other target proteins and protein-like materials have been studied directly from whole cells. For example, Lantibiotics, antimicrobial peptides secreted by Gram-positive bacteria have been detected directly from whole bacteria by MALDI-TOF MS.51 The lantibiotics nisin and lacticin 481 were detected from whole cells and crude supernatants. Surprisingly, better results were reported from whole cells than the supernatants. In this study the presence of variants... 

Potential therapeutic applications of host defense peptides also include the lantibiotic nisin. Indeed, nisin has had an impressive history as a food preservative with FDA approval in 1988 for use in pasteurized, processed cheese spreads. The attractiveness of nisin as a potential therapeutic is also enhanced due to its relative resistance to proteases and broad spectrum Gram-positive antimicrobial activity including multidrug-resistant strains. Biosynexus Inc. has licensed the use of nisin for human clinical applications and Immucell Corp. has licensed the use of Mast Out, an antimastitic nisin-containing product, to Pfizer Animal Health." Indeed, nisin formulations have been used as an active agent in the topical therapies Mast Out and Wipe-Out for bovine mastitis, an inflammatory disorder of the udder that is the most persistent disease in dairy cows." ... 

Lantibiotics. Certain antimicrobial peptides have been identified which contain "unusual" amino acids such as lanthionine, /3-methyllanthionine, dehydroalanine, and jS-methyldehydroalanine. Due to the predominance of lanthionine they have been collectively referred to as "lantibiotics" (26). Among the lactic acid bacteria, two bacteriocins have been identified as lantibiotics, nisin and lacticin 481. Nisin, the first... 

The prototypical lantibiotic, nisin, was discovered in 1928 for its antibacterial properties and has been used as a preservative in dairy products since the 1950s (1). Nisin and other lantibiotics exhibit nanomolar efficacy against many Gram-positive strains of bacteria (2), which include methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci, and oxacillin resistant bacteria. On the other hand, some lantibiotics function as morphogenetic peptides rather than antibiotics and are important for spore formation in streptomycetes (3). Since the structural elucidation of nisin in the early 1970s, extensive research efforts have been directed at understanding the biosynthesis and mode of action of various lantibiotics. 

Figure 2 Mode of action of the prototypical lantibiotic nisin. (a) The peptidoglycan precursor lipid II is composed of an N-acetylglucosamine-p-1,4-N-acetylmuramic acid disaccharide (GIcNAc-MurNAc) that is attached to a membrane anchor of 11 isoprene units via a pyrophosphate moiety. A pentapeptide is linked to the muramic acid. Transglycosylase and transpeptidase enzymes polymerize multiple lipid II molecules and crosslink their pentapeptide groups, respectively, to generate the peptidoglycan. (b) The NMR solution structure of the 1 1 complex of nisin and a lipid II derivative in DMSO (6). (c) The amino-terminus of nisin binds the pyrophosphate of lipid II, whereas the carboxy-terminus inserts into the bacterial membrane. Four lipid II and eight nisin molecules compose a stable pore, although the arrangement of the molecules within each pore is unknown (5).

Peptide communication systems include the competence stimulating factor (CSF) of B. subtilis, which is a pentapeptide (sequence ERGMT) derived from the 5 carboxy-terminal amino acids of the 40-amino-acid peptide encoded by phrC (25). Other systems include the lantibiotic nisin in Lactococcus lactis, which positively regulates its own expression. Staphylococcus... 

Nisin, the prototype and best studied Type A of lantibiotics. Nisin A is a heterode-tic pentacylic peptide (Mr 3353 Da) formed by a single lanthionine (Ala-S-Ala) and four 3-methyllanthionine residues (Abu-... 

The class IA lantibiotic nisin was shown to form ion-permeable channels in the cytoplasmic membrane of susceptible cells, resulting in an increase in the membrane permeabiHty, distmbing the membrane potential and causing an efflux of ATP, amino acids, and essential ions such as potassiiun and magnesium. Ultimately, the biosynthesis of macromolecules and energy production are inhibited resulting in cell death. Nisin does not require a membrane receptor but requires an energized membrane for its activity, which appeared to be dependent on the phospholipid composition of the membrane [67]. 

Mulders JW, Boerrigter LJ, RoUema HS, Siezen RJ, De Vos WM (1991) Identification and characterization of the lantibiotic nisin Z, a natural nisin variant. Eiu J Biochem 201 581-584... 

Engelke G, Gutowski-Eckel Z, Hammehnann M, Entian K-D (1992) Biosynthesis of the lantibiotic nisin genomic organization and membrane localization of the NisB protein. Appl Environ Microbiol 58 3730 - 3743... 

Siegers K, Entian K-D (1995) Genes involved in immunity to the lantibiotic nisin produced by Lactococcus lactis 6F3. Appl Environ Microbiol 61 1081-1089... 

Qiao M, Saris PE (1996) Evidence for a role of Nis T in transport of the lantibiotic nisin produced by Lactococcus lactis N8. FEMS Microbil Lett 144 89-93... 

Dodd HM, Horn N, Gasson MJ. A cassette vector for protein engineering the lantibiotic nisin. Gene 1995 162 163-164. 

Kindrachuk, J., Jenssen, H., Elliott, M., Nijnik, A., Magrangeas-Janot, L., Pasupuleti, M., Thorson, L., Ma, S., Easton, D.M., Bains, M., 2013. Manipulation of innate immunity by a bacterial secreted peptide lantibiotic nisin Z is selectively immunomodulatory. Innate Immunity 19, 315-327. 

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