Structure-activity relationships in the peptide antibiotic nisin: role of dehydroalanine 5

Chan, Weng C.; Dodd, Helen M.; Horn, Nikki; Maclean, Kyle; Lian, Lu‐Yun; Bycroft, Barrie W.; Gasson, Michael J.; Roberts, Gordon C. K.

doi:10.1128/aem.62.8.2966-2969.1996

Cited by 67 publications

(41 citation statements)

References 23 publications

(30 reference statements)

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“…was 2^10-fold lower than nisin Z [67], con¢rming the importance of Dha5 in nisin. Replacement of Dha5 with an alanine did not dramatically a¡ect the pore-forming activity of nisin against vegetative cells, but nisin Ala5 was much less e¡ective as an inhibitor of spore outgrowth [74]. This provides strong evidence that nisin has two distinct biological activities : inhibition of bacterial growth and inhibition of spore outgrowth, produced by two distinct molecular mechanisms.…”

Section: Unusual Amino Acidsmentioning

confidence: 87%

Lantibiotics: structure, biosynthesis and mode of action

McAuliffe¹,

Ross²,

Hill³

2001

FEMS Microbiol Rev

549

312

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The lantibiotics are a group of ribosomally synthesised, post-translationally modified peptides containing unusual amino acids, such as dehydrated and lanthionine residues. This group of bacteriocins has attracted much attention in recent years due to the success of the well characterised lantibiotic, nisin, as a food preservative. Numerous other lantibiotics have since been identified and can be divided into two groups on the basis of their structures, designated type-A and type-B. To date, many of these lantibiotics have undergone extensive characterisation resulting in an advanced understanding of them at both the structural and mechanistic level. This review outlines some of the more recent developments in the biochemistry, genetics and mechanism of action of these peptides.

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Section: Unusual Amino Acidsmentioning

confidence: 87%

Lantibiotics: structure, biosynthesis and mode of action

McAuliffe¹,

Ross²,

Hill³

2001

FEMS Microbiol Rev

549

312

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“…In subtilin, the exchange of the Dha residue at position 5 for Ala led to the loss of sporicidal activity but not pore-forming antibacterial activity (13). Similarly, the replacement of Dha-5 by alanine has no effect on the activity of nisin as an inhibitor of bacterial growth but does drastically decrease its level of activity as an inhibitor of spore outgrowth (6). Dodd et al (8) showed that in nisin both Dha-5 and Dha-33 are not critical for activity.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Study of the Lantibiotic Mutacin II from Streptococcus mutans T8 by a Gene Replacement Strategy

Chen¹,

Novák²,

Kirk

et al. 1998

Appl Environ Microbiol

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Mutacin II, elaborated by group II Streptococcus mutans, is a ribosomally synthesized and posttranslationally modified polypeptide antibiotic containing unusual thioether and didehydro amino acids. To ascertain the role of specific amino acid residues in mutacin II antimicrobial activity, we developed a streptococcal expression system that facilitates the replacement of themutA gene with a single copy of a mutated variant gene. As a result, variants of mutacin II can be designed and expressed. The system was tested by constructing the following mutant peptides: ΔN1, V7A, P9A, T10A, T10S, C15A, C26A, and C27A. All of these mutacin II variants except ΔN1 and T10A, which were not secreted, were isolated, and their identities were verified by mass spectrometry. Variants P9A, C15A, C26A, and C27A failed to exert antimicrobial activity. Because the P9A and T10A variants comprise the “hinge” region of mutacin II, these observations suggest that in addition to the thioether and didehydro amino acids, the hinge region is essential for biological activity and biosynthesis or export of the peptide. Tandem mass spectrometry of the N-terminal part of the wild-type molecule and its C15A variant confirmed that the threonine at position 10 is dehydrated and present as a didehydrobutyrine residue. This analysis of the active T10S variant further suggested that a didehydro amino acid at this position is specific for antimicrobial activity and that the biosynthetic machinery does not discriminate between threonine and serine. In contrast, the lack of production of mutacin variants with alanine substituted for threonine at position 10, as well as the deletion of asparagine at the N terminus (ΔN1), indicates that specific residues in the propeptide may be crucial for certain steps in the biosynthetic pathway of this lantibiotic.

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“…Nisin A is referred to as nisin in this paper. The molecule possesses bactericidal activity against a broad spectrum of Gram-positive bacteria or their spores (Hurst, 1981;Chan et al, 1996). The primary target is the cytoplasmic membrane of sensitive bacteria, in which membrane-potentialdependent transient pores can be formed, leading to an efflux of small molecules and a collapse of the protonmotive force, eventually resulting in cell death (Ruhr & Sahl, 1985;Henning et al, 1986;Kordel & Sahl, 1986;Sahl et al, 1987;Driessen et al, 1995).…”

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confidence: 99%

Structural Features of the Final Intermediate in the Biosynthesis of the Lantibiotic Nisin. Influence of the Leader Peptide

Hooven¹,

Rollema²,

Siezen³

et al. 1997

Biochemistry

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The antimicrobial membrane-interacting polypeptide nisin is a prominent member of the lantibiotic family, the members of which contain thioether-bridged residues called lanthionines. To gain insight into the complex biosynthesis and the structure/function relationship of lantibiotics, the final intermediate in the biosynthesis of nisin A was studied by nuclear magnetic resonance spectroscopy. In aqueous solution the leader peptide part of this precursor adopts predominantly a random coil structure, as does the synthetic leader peptide itself. The spatial structure of the fully modified nisin part of the precursor is similar to that of nisin in water. The leader peptide part does not interact with the nisin part of the precursor molecule. Thus, these two parts of the precursor do not influence each other's conformation significantly. The conformation of the precursor was also studied while complexed to micelles of dodecylphosphocholine, mimicking the primary target of the antimicrobial activity of nisin, i.e. the cytoplasmic membrane. The location of the molecule relative to the micelles was investigated by using micelle-inserted spin-labeled 5-doxylstearic acid. It was observed that the N-terminal half of the nisin part of the precursor interacts in a different way with micelles than does the corresponding part of mature nisin, whereas no significant differences were found for the C-terminal half of the nisin part. In this model system the leader peptide is in contact with the micelles. It is concluded that the strongly reduced in vivo activity of the precursor molecule relative to that of nisin is not caused by a difference in the spatial structure of nisin and of the corresponding part of precursor nisin in water or by a shielding of the membrane interaction surface of the nisin part of the precursor by the leader peptide. Probably a different interaction of the N-terminal part of the nisin region with membranes contributes to the low activity by preventing productive insertion. The residues of the leader peptide part just next to the nisin part are likely to contribute most to the low activity of the precursor.

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Structure-activity relationships in the peptide antibiotic nisin: role of dehydroalanine 5

Cited by 67 publications

References 23 publications

Lantibiotics: structure, biosynthesis and mode of action

Lantibiotics: structure, biosynthesis and mode of action

Structure-Activity Study of the Lantibiotic Mutacin II from Streptococcus mutans T8 by a Gene Replacement Strategy

Structural Features of the Final Intermediate in the Biosynthesis of the Lantibiotic Nisin. Influence of the Leader Peptide

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