Biosynthesis and Biological Activities of Lantibiotics with Unique Post‐Translational Modifications

Abstract

Lantibiotics are biologically active peptides which contain the thioether amino acid lanthionine as well as several other modified amino acids. They can be broadly divided into two groups on the basis of their structures : type-A lantibiotics are elongated, amphiphilic peptides, while type-B lantibiotics are compact and globular. In the last decade there has been a marked increase in research interest in these peptides due both to the novel biosynthetic mechanisms by which they are produced, as well as to their potential applications. Lantibiotics are synthesised on the ribosome as a prepeptide which undergoes several post-translational modification events, including dehydration of specific hydroxyl amino acids to form dehydroamino acids, addition of neighbouring sulfhydryl groups to form thioethers and, in specific cases, other modifications such as introduction of D-alanine residues from L-serine, formation of lysinoalanine bridges, formation of novel N-terminal blocking groups and oxidative decarboxylation of a Cterminal cysteine. The genetic elements responsible for these specific modification reactions encode unique enzymes with hitherto unknown reaction mechanisms. Production of these peptides also requires accessory proteins including processing proteases, translocators of the ATP-binding cassette transporter family, regulatory proteins and dedicated producer self-protection mechanisms. While the principle biological activity of most type-B lantibiotics appears to be directed at the inhibition of enzyme functions, the type-A lantibiotics kill bacterial cells by forming pores in the cytoplasmic membrane.Keywords. Lantibiotics ; structures and conformations ; genetics and biosynthesis ; modes of action ; antibiotic peptides.Lantibiotics are a group of unique antibiotic peptides which are produced by and primarily act on Gram-positive bacteria. The term lantibiotics was introduced as an abbreviation for lanthionine-containing antibiotic peptides ) and refers to the most prominent features of this group, which are the strong antibacterial activity and the intra-molecular rings formed by the thioether amino acids lanthionine (Lan) and 3-methyllanthionine (MeLan). In addition to these unusual residues, the dehydrated amino acids 2,3-didehydroalanine (Dha) and 2,3-didehydrobutyrine (Dhb) occur commonly in lantibiotics, whereas further modified residues such as lysinoalanine, S-aminOVinyl-D-CySteine, S-aminovinyl-D-methylcysteine and erythro-3-hydroxyaspartic acid are only found in individual peptides. These unusual amino acids are synthesised by post-translational side-chain modifications of ribosomally produced precursor peptides. It is the presence of these residues, their influence on the structure and activity of the peptides and their unique

ThedltOperon ofBacillus cereusIs Required for Resistance to Cationic Antimicrobial Peptides and for Virulence in Insects

“…Studies of the role of dlt in rodent infection models showed that this operon was required for host-pathogen interactions involving L. monocytogenes, S. aureus, B. anthracis, and S. agalactiae (1,13,34,78). We show here, for the first time, that the dlt locus of the human opportunistic and entomopathogenic bacterium B. cereus ATCC 14579 is important for protection against insect humoral immune mediators, in- AMPs constitute families of bactericidal peptides widely produced by microbes to inhibit the growth of competing strains (14,81) and by higher organisms as part of the humoral immune response to bacterial infections (42,95). Many AMPs are thought to act by accumulating in the cytoplasmic membrane to a critical concentration allowing the assembly of structures that permeabilize the cell (41,42).…”

In Vitro Reconstitution and Substrate Specificity of a Lantibiotic Protease

“…Several roles have been proposed, including acting as a scaffold for the modification enzymes, allowing the prepeptide to be recognized for export, or protecting the producing organism (9). The leader sequences within each lantibiotic class share several conserved residues that could contribute to these functions ( Figure 5).…”

“…The role(s) of the leader peptide in lantibiotic biosynthesis has been the subject of much speculation (8,9). It may act in a protective role for the producing organism, as its removal is required for bioactivity (10)(11)(12)(13)(14)(15).…”

Characteristics of the bovicin HJ50 gene cluster in Streptococcus bovis HJ50

“…The lantibiotics represent a diverse family of bacterially produced antimicrobial peptides Sahl et al, 1995;van Kraaij et al, 1999). They are characterized by the presence of lanthionine and b-methyllanthionine, which form intramolecular thioether rings.…”