A Glycosylated, Labionin-Containing Lanthipeptide with Marked Antinociceptive Activity

Abstract

Among the growing family of ribosomally synthesized, post-translationally modified peptides, particularly intriguing are class III lanthipeptides containing the triamino acid labionin. In the course of a screening program aimed at finding bacterial cell wall inhibitors, we discovered a new lanthipeptide produced by an Actinoplanes sp. The molecule, designated NAI-112, consists of 22 amino acids and contains an N-terminal labionin and a C-terminal methyl-labionin. Unique among lanthipeptides, it carries a 6-deoxyhexose moiety N-linked to a tryptophan residue. Consistently, the corresponding gene cluster encodes, in addition to the LanKC enzyme characteristic of this lanthipeptide class, a glycosyl transferase. Despite possessing weak antibacterial activity, NAI-112 is effective in experimental models of nociceptive pain, reducing pain symptoms in mice in both the formalin and the chronic constriction injury tests. Thus, NAI-112 represents, after the labyrinthopeptins, the second example of a lanthipeptide effective against nociceptive pain.

Expanded Natural Product Diversity Revealed by Analysis of Lanthipeptide-Like Gene Clusters in Actinobacteria

“…Conversely, many others may have other biological activities that remain to be revealed by future studies. Indeed, most of the class III lanthipeptides reported thus far from Actinobacteria have no or weak antimicrobial activities, and quite a few have anti-allodynic/antinociceptive activity (38,74) or morphogenetic activities (75). Since the venezuelins did not display antimicrobial activity in a previous study (16), class IV lanthipeptides may also have activities that would have eluded antimicrobial screens.…”

“…This phylum has been the source and/or inspiration for the majority of pharmaceutically useful natural products (24,25). Although Actinobacteria constitute only a small proportion of known lanthipeptide producers, they encode a diverse set of posttranslational modifications that have not been observed for lanthipeptides from other phyla (2) (e.g., lysinoalanine formation in cinnamycin [26], tryptophan chlorination and proline dihydroxylation in microbisporicin [27,28, also called NAI-107 [29], and glycosylation in NAI-112 [30]). The unique modifications in actinobacterial lanthipeptide biosynthesis suggest great potential for exploring unknown lanthipeptide chemical space in this phylum.…”

Lantibiotics produced by Actinobacteria and their potential applications (a review)

“…Actinobacterial bacteriocins inhibit the growth of species related to the producer, such as michiganin A [13], although many of them possess a broad spectrum of inhibitory activity that includes non-related bacteria (microbisporicin), protozoans (thiostrepton), yeasts and fungi (cinnamycin) and viruses (labyrinthopeptin A1 and duramycin) [14][15][16][17][18]. In addition to antimicrobial activity, some actinobacterial bacteriocins and their semisynthetic derivatives also exhibit anti-inflammatory [19][20][21], anti-allergic [20], antitumour [22][23][24] and antinociceptive activities [25,26], and may also act in blood pressure regulation [19,27]. Some of these peptides have already found clinical applications, such as thiostrepton, a thiopeptide used in dermatologic ointment for veterinary use [28], and others are in stages of pre-clinical and clinical trials, such as NAI-107, NAI-112 [29] and lancovutide/duramycin (https://clinicaltrials.gov/ct2/show/study/ NCT00671736?term=Lancovutide&rank=1; accessed September 17,2016), which reinforces the great potential of practical application of bacteriocins produced by Actinobacteria.…”

“…Therefore, like LabA2, NAI-112 has potential to be used for pain relief applications. However, the mechanism of action of NAI-112 as antinociceptive agent has not been established yet [25].…”

Actinoplanes Swims into the Molecular Age

“…Actinoplanes species are a rich source of natural products (6)(7)(8)(9)(10), including the clinically important antibiotic teicoplanin (11) and the alpha-glucosidase inhibitor acarbose, a potent drug used worldwide in the treatment of type 2 diabetes (12). The substrate mycelium of Actinoplanes colonies consists of branching vegetative hyphae and is similar in appearance to that of Streptomyces.…”