Invited ReviewCombination of antibiotic mechanisms in lantibiotics
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;
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