Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

Arianna Tocchetti,Marianna Iorio,Angelo Reggiani,Zeeshan Hamid,Andrea Armirotti,Stefano Donadio

doi:10.3390/molecules26226764

Arianna Tocchetti, Marianna Iorio + Show 4 more

Open Access

https://doi.org/10.3390/molecules26226764

Copy DOI

Abstract

NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that Staphylococcus aureus can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive S. aureus strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.

Highlights

IntroductionSynthesized and post-translationally modified peptides, or RiPPs, form a diverse group of natural products characterized by a peptide skeleton that can undergo a number of post-translational modifications [1]
The results from the lipidomic experiments in mice, from the binding assay analyzed in MS and from the analysis of the S. aureus mutants resistant to NAI-112, are consistent with the hypothesis that NAI-112 binds to one or more phosphate-containing lipids and, by doing so, interferes with the processing of these lipids by relevant enzymes
This interference translates in lower lysophosphatidic acids (LPAs) levels

Summary

Introduction

Synthesized and post-translationally modified peptides, or RiPPs, form a diverse group of natural products characterized by a peptide skeleton that can undergo a number of post-translational modifications [1]. In the past 20 years, new members have been added to this class of secondary metabolites, mostly thanks to the development of genome-mining tools to detect RiPP biosynthetic gene clusters in the growing microbial genome databases. Over 20 different RiPP families are known, each carrying unique chemical features [2]. This high structural diversity is due to the various post-translational modifications that impart new chemical functionalities on the precursor peptides, leading to core peptides that carry multiple variable sites [3].

Methods

Results

Conclusion