Lantibiotics: Mode of Action, Biosynthesis and Bioengineering

Abstract

Lantibiotics are gene-encoded peptides that contain intramolecular ring structures, introduced through the thioether containing lanthionine and methyllanthionine residues. The overwhelming majority of the lantibiotics shows antibacterial activity. Some lantibiotics, e.g. nisin, are characterized by a dual mode of action. These peptides form a complex with the ultimate cell wall precursor lipid II, thereby inhibiting cell wall biosynthesis. The complexes then aggregate, incorporate further peptides and form a pore in the bacterial membrane. Recent results show that complexing of lipid II is widespread among lantibiotics; however, pore formation depends on the overall length of the peptide and the lipid composition of the test strain membrane. In the two-component system of lacticin 3147, the two functions are performed by the two different peptides. The genetic information for production of lantibiotics is organized in gene clusters which contain a structural gene (lanA) for the lantibiotic prepeptide. The modifications are introduced by one biosynthetic enzyme (LanM) or a combination of a dehydratase (LanB) and a cyclase (LanC). These enzymes have been in the focus of recent bioengineering studies: The structure of NisC has been resolved, the reaction mechanism of LctM was elucidated and the active site residues were characterized by mutagenesis studies. In vitro modification systems have successfully been used to introduce thioether rings into other biologically active peptides. Furthermore, variant lantibiotics with enhanced properties have been engineered and at least one promising new lantibiotic with strong activity against multiresistant pathogens has been described.

Fundamental functionality: recent developments in understanding the structure–activity relationships of lantibiotic peptides

“…Lantibiotics are synthesized by the ribosome with an N-terminal leader sequence and then they are heavily posttranslationally modified. 4 The leader sequence is believed to keep the peptides inactive while inside the producing bacterial cell and to act as a handle for recognition by modification enzymes. 5 Many of these peptides are extremely potent antibacterial agents with minimum inhibitory concentrations in the nM range.…”

“…4 Group A contains peptides that are elongated, whereas group B contains peptides that are more compact and globular. Group A is further subdivided into AI and AII, wherein the lan and melan of the peptides in AI are produced by two modification enzymes (LanB and LanC), whereas the lan and melan of the peptides in AII are produced by a single modification enzyme (LanM).…”

“…6 Nisin also shows considerable promise as a human therapeutic, especially for the treatment of drug-resistant bacterial infections. 7 As nisin SAR studies have been extensively reviewed, 4,6,7,11,12 we have chosen to limit this discussion to several recent studies.…”

Evolution of lanthipeptide synthetases

“…1) (6)(7)(8)(9). Many lanthipeptides, such as the commercially used food preservative nisin, have potent antimicrobial activity and are termed lantibiotics.…”

Cloning and Analysis of the Planosporicin Lantibiotic Biosynthetic Gene Cluster of Planomonospora alba

“…Lanthipeptides are characterized by the presence of the ring-forming thioether amino acids lanthionine (Lan) and/or 3-methyl-lanthionine (MeLan) (Fig. 1A) (2). These nonproteogenic amino acids constrain the molecule into a defined structural conformation that serves the dual role of promoting target specificity while resisting proteolytic degradation (5).…”