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 C‐terminal 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.

Temporin A Alone and in Combination with Imipenem Reduces Lethality in a Mouse Model of Staphylococcal Sepsis

“…The mechanism of this positive interaction remains largely unknown, although it might be due to the contemporaneous effect of temporin A and imipenem on PG. The peptide might act by inserting itself into the cytoplasmic membrane and triggering the activity of bacterial murein hydrolases, resulting in damage or degradation of PG and lysis of the cell [16,19,34]. The probable role of temporin A in such synergy is its rapid permeabilization of the bacterial membrane, which allows enhanced penetration and activity of imipenem.…”

The dual role of bacteriocins as anti- and probiotics

“…Nisins have a dual mode of action: (1) They bind to lipid II, the main transporter of peptidoglycan subunits from the cytoplasm to the cell wall, and therefore prevent correct cell wall synthesis, leading to cell death, and (2) they employ lipid II as a docking molecule to initiate a process of membrane insertion and pore formation that leads to rapid cell death (Wiedemann et al 2001). Type B lantibiotics, such as mersacidin (Twomey et al 2002), kill by interfering with cellular enzymatic reactions, such as cell wall synthesis (Pag and Sahl 2002; Sahl and Bierbaum 1998; Sahl et al 1995). Another subgroup is composed of two-component lantibiotics, such as lacticin 3147 (Wiedemann et al 2006), consisting of two lantibiotic peptides that synergistically display antimicrobial activity (Ryan et al 1998).…”

High resolution crystal structure of PedB: a structural basis for the classification of pediocin-like immunity proteins

“…Most bacteriocins are generally synthesized as prepeptides and can be classified into several classes depending on their post-translational processing and the mode of action [1-3]. Type I bacteriocins, of which a nisin is most well-known, undergo post-translational modifications such as formation of dehydrated residues and lanthionine bridges [4]. In contrast, type IIa bacteriocins are matured by simple cleavage of a leader peptide and characterized by a conserved YGNGVXC motif in the N-terminus [5-7].…”