Influence of nisin hinge-region variants on lantibiotic immunity and resistance proteins

Zaschke-Kriesche, Julia; Reiners, Jens; Lagedroste, Marcel; Smits, Sander H. J.

doi:10.1016/j.bmc.2019.07.014

Cited by 17 publications

(13 citation statements)

References 57 publications

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“…Another important region involved in nisin bioactivity is the hinge region, at positions 21-23 29, 30 . The hinge region consists of the three amino acids (NMK in nisin A, AIK in nisin P) that are responsible for reorientation after binding with lipid II to penetrate into the target cell membrane 31 and importance in nisin antimicrobial activity has been established through bioengineering studies 30–33 . These studies suggest a preference for small, chiral amino acids in that region 32 .…”

Section: Discussionmentioning

confidence: 99%

First evidence of production of the lantibiotic nisin P

García-Gutiérrez

O’Connor

Saalbach

et al. 2019

Preprint

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15Nisin P is a natural nisin variant, the genetic determinants for which were previously identified 16 in the genomes of two Streptococcus species, albeit with no confirmed evidence of production. 17 Here we describe Streptococcus agalactiae DPC7040, a human fecal isolate, which exhibits 18 antimicrobial activity against a panel of gut and food isolates by virtue of producing nisin P. 19 Nisin P was purified, and its predicted structure was confirmed by nanoLC-MS/MS, with both 20 the fully modified peptide and a variant without rings B and E being identified. Additionally, 21 we compared its spectrum of inhibition and minimum inhibitory concentration (MIC) with that 22 of nisin A and its antimicrobial effect in a fecal fermentation in comparison with nisin A and 23 H. We found that its antimicrobial activity was less potent than nisin A and H, and we propose 24 a link between this reduced activity and the peptide structure. 25 26 Keywords: nisin, antimicrobial, structure-activity relationship, fecal microbiome, 27 Structurally, nisin is classified as a lantibiotic because it contains lanthionine (Lan), an unusual 36 amino acid formed by two alanine residues linked by a sulphur atom through their β-carbon 4 . 37Other unusual amino acids present in nisin are dehydroalanine (Dha), dehydrobutyrine (Dhb) 38 3 3 and β-methyl-lanthionine 4 . Nisin activity and stability are closely related to its structure and 39 can be altered by pH changes. Increasing pH results in decreasing activity as a consequence of 40 alterations in structure, therefore, nisin is more stable at lower pH. Nisin is heat-stable and also 41 exhibits high stability at low temperatures, which makes it suitable for freeze-storage 7 . 42Nisin has nine reported natural variants ( Figure 1, Table 1). Nisin A is the most studied nisin 43 as it was the first one purified 8 . Nisin Z is considered the first natural variant of nisin A; it 44 differs in the presence of an asparagine amino acid in position 27 instead of a histidine residue 45 9 . This substitution has very little effect on antimicrobial activity, thermal and pH stability 46 compared to nisin A, but affects the solubility of the molecule, with nisin Z being more soluble 47 at neutral pH 10 . A study of its distribution also revealed that nisin Z is more widespread than 48 nisin A 10 . Nisin F, produced by L. lactis isolated from a fish gut, also has asparagine and valine 49 in positions 21 and 30 11 . Nisin Q was identified in an environmental L. lactis isolate and differs 50 from nisin A due to the presence of valine, leucine, asparagine and valine in positions 15, 21, 51 27 and 30, respectively 12 . Nisin U and U2 were the first variants found to be produced by a 52 species other than L. lactis 13 ; they are produced by Streptococcus uberis strain 42, isolated 53 from bovine mammary secretions 14 , and differ to nisin A by nine and ten amino acids, 54 respectively. Nisin H, produced by Streptococcus hyointestinalis was the first variant isolated 55 from a mammalian gastrointestin...

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Section: Discussionmentioning

confidence: 99%

First evidence of production of the lantibiotic nisin P

García-Gutiérrez

O’Connor

Saalbach

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Another important region involved in nisin bioactivity is the hinge region, at positions 21-23 28,29 . The hinge region consists of the three amino acids (NMK in nisin A, AIK in nisin P) that are responsible for reorientation after binding with lipid II to penetrate into the target cell membrane 30 and importance in nisin antimicrobial activity has been established through bioengineering studies [29][30][31][32] . These studies suggest a preference for small, chiral amino acids in that region 31 .…”

Section: Discussionmentioning

confidence: 99%

First evidence of production of the lantibiotic nisin P

García-Gutiérrez

O’Connor

Saalbach

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Nisin P is a natural nisin variant, the genetic determinants for which were previously identified in the genomes of two Streptococcus species, albeit with no confirmed evidence of production. Here we describe Streptococcus agalactiae DPC7040, a human faecal isolate, which exhibits antimicrobial activity against a panel of gut and food isolates by virtue of producing nisin P. Nisin P was purified, and its predicted structure was confirmed by nanoLC-MS/MS, with both the fully modified peptide and a variant without rings B and E being identified. Additionally, we compared its spectrum of inhibition and minimum inhibitory concentration (MIC) with that of nisin A and its antimicrobial effect in a faecal fermentation in comparison with nisin A and H. We found that its antimicrobial activity was less potent than nisin A and H, and we propose a link between this reduced activity and the peptide structure.Nisin is a small peptide with antimicrobial activity against a wide range of pathogenic bacteria. It was originally sourced from a Lactococcus lactis subsp. lactis isolated from a dairy product 1 and is classified as a class I bacteriocin, as it is ribosomally synthesised and post-translationally modified 2 . Nisin has been studied extensively and has a wide range of applications in the food industry, biomedicine, veterinary and research fields 3-6 . It is approved as a food preservative by the Food and Agriculture Organization and is Generally Recognized As Safe (GRAS) by the United States Food and Drug Administration 4 .Structurally, nisin is classified as a lantibiotic because it contains lanthionine (Lan), an unusual amino acid formed by two alanine residues linked by a sulphur atom through their β-carbon 4 . Other unusual amino acids present in nisin are dehydroalanine (Dha), dehydrobutyrine (Dhb) and β-methyl-lanthionine 4 . Nisin activity and stability are closely related to its structure and can be altered by pH changes. Increasing pH results in decreasing activity as a consequence of alterations in structure, therefore, nisin is more stable at lower pH. Nisin is heat-stable and also exhibits high stability at low temperatures, which makes it suitable for freeze-storage 7 .Nisin has nine reported natural variants (Fig. 1, Table 1). Nisin A is the most studied nisin as it was the first one purified 8 . Nisin Z is considered the first natural variant of nisin A; it differs in the presence of an asparagine amino acid in position 27 instead of a histidine residue 9 . This substitution has very little effect on antimicrobial activity, thermal and pH stability compared to nisin A, but affects the solubility of the molecule, with nisin Z being more soluble at neutral pH 10 . A study of its distribution also revealed that nisin Z is more widespread than nisin A 10 . Nisin F, produced by L. lactis isolated from a fish gut, also has asparagine and valine in positions 21 and 30 11 . Nisin Q was identified in an environmental L. lactis isolate and differs from nisin A due to the presence of valine, leucine, asparagine and va...

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“…Although most variants with shorter or larger hinge length are less active than the wild type, some variants (+2, +1, −1, −2) exhibited higher antimicrobial activity than the wild type nisin A in agar-well-diffusion assays against L. lactis MG1363, Listeria monocytogenes , Enterococcus faecalis VE14089, Bacillus sporothermodurans IC4, and Bacillus cereus 4153. In addition, an extended nisin A variant of the hinge region ( 2 0 NMKIV 24 ) has been introduced, bypassing the human pathogen’s lantibiotic resistance while showing a slight decrease in antimicrobial activity ( Zaschke-Kriesche et al, 2019 ). In this context, Figure 3 represents different variants of nisin produced by classical protein engineering together with a graphical representation of the mechanism of action of this bioactive peptide.…”

Section: The Feasibility Of Genetic Engineering To Produce More Potenmentioning

confidence: 99%