Characterization of New Class III Lantibiotics—Erythreapeptin, Avermipeptin and Griseopeptin from Saccharopolyspora erythraea, Streptomyces avermitilis and Streptomyces griseus Demonstrates Stepwise N‐Terminal Leader Processing

Abstract

Lantibiotics are a large group of ribosomally synthesized peptides post-translationally modified to incorporate the amino acid lanthionine. They are classified, according to their biosynthetic pathway and bioactivity, into three major subtypes. Of Actinomycetes type III lantibiotics, only four peptides (SapB, SapT, LabA1, and LabA2) have been described and structurally characterized, although homologous gene clusters are abundant in other Actinomycetes. All these gene clusters share a similar architecture with a characteristic Ser/Ser/Cys motif in precursor peptides, which has previously been suggested to act as a precursor for lanthionine (SapB) and labionin (LabA2) rings. Mass spectrometry screening led to the discovery and characterization of three new representatives of type III lantibiotics: Avermipeptin (Avi), Erythreapeptin (Ery), and Griseopeptin (Gri) from Streptomyces avermitilis DSM 46492, Saccharopolyspora erythraea NRRL 2338, and Streptomyces griseus DSM 40236, respectively. Apart from the assignment of these peptides to their corresponding gene clusters, additional investigations on Avi, Ery and Gri peptides indicate stepwise leader processing by putative aminopeptidase-like protease(s), thus yielding mixtures of differently N-terminal-processed lantibiotic peptides. Similar peptide processing was observed for a heterologously expressed eryth biosynthetic gene cluster expressed in a Streptomyces host system. Remarkably, all isolates of the new type III lantibiotics contain both the amino acids lanthionine and labionin, thus implying dual-mode cyclase activity of the processing lyase-kinase-cyclase enzymes. These findings have implications for the structures and maturation of other type III lantibiotics from Actinomycetes.

Evolution of lanthipeptide synthetases

“…Many, but not all, LanKCs synthesize labionins (SI Appendix, Fig. S11), which are thus far found exclusively for class III lanthipeptides (34)(35)(36).…”

“…S12). In addition, recently characterized class III peptides contain both lanthionine and labionin (36), and the biosynthetic enzymes of these peptides are distributed in different subclades of the LanKC clade (SI Appendix, Fig. S12).…”

Cerecidins, Novel Lantibiotics from Bacillus cereus with Potent Antimicrobial Activity

“…Isolation of antimicrobial peptides from agar plates. To obtain antimicrobial peptides that were produced by B. cereus As 1.1846 containing plasmid pHY-P aprN -cerM, an agar-guided isolation was applied as described by Völler et al (32). Briefly, supernatant of overnight bacterial culture was added onto agar plates of indicator strain M. flavus NCIB8166.…”

A Glycosylated, Labionin-Containing Lanthipeptide with Marked Antinociceptive Activity

“…Since the discovery of the labyrinthopeptins, the first Lab-containing lanthipeptides, 8 this unusual amino acid has been found in few other lanthipeptides. 9,10 In the course of a screening program for peptidoglycan inhibitors, we unexpectedly discovered a labionin-containing lanthipeptide, designated NAI-112, which possesses unique structural properties. Since labyrinthopeptins have been reported to exert potent antiallodynic effects in the spinal nerve injury model of neuropathic pain, 11 we also assessed whether NAI-112 has antinociceptive/antiallodynic activity in two different experimental models of inflammatory pain.…”