Elsevier

Il Farmaco

Volume 57, Issue 8, 31 July 2002, Pages 685-691
Il Farmaco

Invited Review
Combination of antibiotic mechanisms in lantibiotics

https://doi.org/10.1016/S0014-827X(02)01208-9Get rights and content

Abstract

Recent studies on the mode of action have revealed exciting features of multiple activities of nisin and related lantibiotics making these peptides interesting model systems for the design of new antibiotics (Molec. Microbiol. 30 (1998) 317; Science 286 (1999) 2361; J. Biol. Chem. 276 (2001) 1772.). In contrast to other groups of antibiotic peptides, the lantibiotics display a substantial degree of specificity for particular components of bacterial membranes. Mersacidin and actagardine were shown to bind with high affinity to the lipid coupled peptidoglycan precursor, the so-called lipid II, which prevents the polymerisation of the cell wall monomers into a functional murein sacculus. The lantibiotics nisin and epidermin also bind tightly to this cell wall precursor; however, for these lantibiotics the binding of lipid II has two consequences. Like with mersacidin blocking of lipid II inhibits peptidoglycan biosynthesis; in addition, lipid II is used as a specific docking molecule for the formation of pores. This combination of lethal effects explains the potency of these peptides, which are active in nanomolar concentration. Other type-A lantibiotics are believed to also use docking molecules for pore formation, although identification of such membrane components has not yet been achieved.

Introduction

Lantibiotics are antimicrobial peptides produced by a wide range of Gram-positive bacteria. They represent a subgroup of bacteriocins, which is characterised by the presence of unique modified amino acids, particularly dehydroamino acids and the thioether amino acids lanthionine (Lan) and 3-methyllanthionine (MeLan). In contrast to “classical” peptide antibiotics produced by multienzyme complexes [1], [2], lantibiotics are ribosomally synthesised as precursor peptides, which are subsequently converted into the biologically active peptides through post-translational modifications. A number of modified amino acids have been found in lantibiotics including e.g.: meso-lanthionine (Lan), threo-β-methyllanthionine (MeLan), S-[(Z)-2-aminovinyl]-d-cysteine (AviCys), S-[(Z)-2-aminovinyl]-3-methyl-d-cysteine (AviMeCys), 2,3-didehydroalanine (Dha), 2,3-didehydrobutyrine (Dhb) and d-alanine (Fig. 1). The reaction of Dha or Dhb with a cysteine residue results in the formation of the intramolecular ring-structures Lan and MeLan, respectively. The post-translationally modified propeptides are activated by proteases and exported from the producing cells.

Lantibiotics do not form a homogeneous group. Regarding the enzymes taking part in modifications as well as export and processing, two different classes of lantibiotics can be distinguished [3]. Class I lantibiotics are modified by two enzymes, LanB and LanC, catalysing the dehydration of hydroxyamino acids and the formation of the thioether rings, respectively; proteolytic processing and export from the producing cells are performed by dedicated proteases LanP and ABC-transporters LanT. Class II lantibiotics are modified by only one enzyme, LanM, and secreted and activated through hybrid ABC-transporters with an additional proteolytic domain at their N-terminus. According to a proposal of Jung [4], based on the information on structures and modes of action available at that time, the lantibiotics were grouped into the elongated, amphiphilic, screw shaped, membrane-depolarising type-A peptides and the small, globular and enzyme inhibitory type-B lantibiotics. However, in the last decade a significant number of new lantibiotics with intermediate features has been characterised, making a categorisation on the basis of structural and functional features more difficult.

Section snippets

Type-A lantibiotics—formation of target independent pores

Type-A lantibiotics are typically active against Gram-positive strains; Gram-negative bacteria are only affected when the outer membrane is disrupted e.g. by ion chelators such as EDTA or citrate [5], [6]. The most prominent member of the Type-A group is nisin (Fig. 2). The first report on the mechanism of this prototype type-A lantibiotic dates back to 1960 when Ramseier [7] observed leakage of UV-absorbing intracellular compounds from treated cells and suggested a detergent effect. Subsequent

Type-A lantibiotics—formation of target mediated pores

Since type-A lantibiotics can act on artificial membranes, binding to specific receptors in the cell membrane is not a prerequisite for activity per se [33]; therefore, a concept of specific targets being involved in the membrane interaction had not been considered. However, for nisin, a finite number of binding sites and specific antagonisation of nisin activity by the inactive N-terminal nisin fragment 1–12 had been observed [34], indicating that a defined binding site may be blocked by the

Additional activities of type-A lantibiotics

In addition to pore formation and inhibition of the cell wall biosynthesis, nisin and the related cationic lantibiotic Pep5 have been shown to induce autolysis of susceptible staphylococcal cells, resulting in massive cell wall degradation, most markedly in the area of the septa between dividing daughter cells. The peptides are able to release two cell wall hydrolysing enzymes, an N-acetylmuramoyl-l-alanine amidase and an N-acetylglucosaminidase, which are strongly cationic proteins binding to

Type-B lantibiotics—mersacidin and actagardine

The type-B lantibiotics mersacidin and actagardine are active against a variety of Gram-positive bacteria, with actagardine being most effective against streptococci and obligate anaerobes [49], [50], while mersacidin (Fig. 2) is almost equally active against staphylococci, streptococci, bacilli, clostridia, corynebacteria, peptostreptococci, and Propionibacterium acnes [34], [51], [52]. Gram-negative bacteria are not susceptible, since peptides cannot pass the outer membrane of bacteria;

References (63)

  • F. Märki et al.

    Mode of action of the lanthionine-containing peptide antibiotics duramycin, duramycin B and C, and cinnamycin as indirect inhibitors of phospholipase A2

    Biochem. Pharmacol.

    (1991)
  • H. Kleinkauf et al.

    Nonribosomal biosynthesis of peptide antibiotics

    Eur. J. Biochem.

    (1990)
  • H. Kleinkauf et al.

    A nonribosomal system of peptide biosynthesis

    Eur. J. Biochem.

    (1996)
  • H.-G. Sahl et al.

    Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from Gram-positive bacteria

    Annu. Rev. Microbiol.

    (1998)
  • G. Jung

    Lantibiotics-ribosomally synthesized biologically active polypeptides containing sulfide bridges and α,β-didehydroamino acids

    Angew. Chem., Int. Ed. Engl.

    (1991)
  • M. Kordel et al.

    Mode of action of the staphylococcinlike peptide Pep5: voltage-dependent depolarization of bacterial and artificial membranes

    J. Bacteriol.

    (1988)
  • K.A. Stevens et al.

    Nisin treatment for inactivation of Salmonella species and other Gram-negative bacteria

    Appl. Environ. Microbiol.

    (1991)
  • H.R. Ramseier

    Die Wirkung von Nisin auf Clostridium butyricum

    Arch. Mikrobiol.

    (1960)
  • E. Ruhr et al.

    Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles

    Antimicrob. Agents Chemotherapy

    (1985)
  • H.-G. Sahl

    Influence of the staphylococcinlike peptide Pep5 on membrane potential of bacterial cells and cytoplasmic membrane vesicles

    J. Bacteriol.

    (1985)
  • R.W. Jack et al.

    The mode of action of SA-FF22, a lantibiotic isolated from Streptococcus pyogenes strain FF22

    Eur. J. Biochem.

    (1994)
  • H.-G. Sahl et al.

    Voltage-dependent depolarization of bacterial membranes and artificial lipid bilayers by the peptide antibiotic nisin

    Arch. Microbiol.

    (1987)
  • F. Schüller et al.

    The peptide antibiotic subtilin acts by formation of voltage-dependent multi-state pores in bacterial and artificial membranes

    Eur. J. Biochem.

    (1989)
  • R. Benz et al.

    Mechanism of channel-formation by lantibiotics in black lipid membranes

  • G. Boheim

    Statistical analysis of alamethicin channels in black lipid membranes

    J. Membr. Biol.

    (1974)
  • G. Ehrenstein et al.

    Electrically gated ionic channels in lipid bilayers

    Q. Rev. Biophys.

    (1977)
  • V. Rizzo et al.

    Alamethicin incorporation in lipid bilayers: a thermodynamic study

    Biochemistry

    (1987)
  • H.W. van den Hooven et al.

    Three-dimensional structure of the lantibiotic nisin in the presence of membrane-mimetic micelles of dodecylphosphocholine and of sodium dodecylsulphate

    Eur. J. Biochem.

    (1996)
  • H.W. van den Hooven et al.

    Surface location and orientation of the lantibiotic nisin bound to membrane-mimicking micelles of dodecylphophocholine and of sodium dodecylsulphate

    Eur. J. Biochem.

    (1996)
  • A.J.M. Driessen et al.

    Mechanistic studies of lantibiotic-induced permeabilization of phospholipid vesicles

    Biochemistry

    (1995)
  • G.N. Moll et al.

    Mechanism of lantibiotic-induced pore formation

    Antonie van Leeuwenhoek Int. J. Gen. Molec. Microbiol.

    (1996)
  • Cited by (31)

    • Case studies: application of lantibiotics as novel drugs

      2023, Lantibiotics as Alternative Therapeutics
    • Sequence-based analysis and prediction of lantibiotics: A machine learning approach

      2018, Computational Biology and Chemistry
      Citation Excerpt :

      Generally, all classes of lantibiotics contain peptides with different bioactivities amongst which antimicrobial activity is of great importance and therefore all four classes are important in antimicrobial research and studies (James et al., 2013). More importantly, lantibiotics have shown to exhibit activity against many nosocomial and clinically-relevant targets such as methicillin resistant Staphylococcus aureus (MRSA) (Kruszewska et al., 2004), vancomycin intermediate S. aureus (VISA) (Castiglione et al., 2008), vancomycin resistant enterococci (VRE) (Hoffmann et al., 2002), Streptococcus pneumoniae (Cotter et al., 2013) as well as Clostridium difficile (Rea et al., 2007). Besides, recently a novel group of lantibiotics called pinensins have been found to be active against some fungal strains (Mohr et al., 2015) as well as other reports that show some lantibiotics are active against Escherichia coli and Salmonella typhimurium (Prudêncio et al., 2015; Stevens et al., 1991).

    View all citing articles on Scopus
    View full text